Analogs for the treatment of disease

ABSTRACT

The disclosure provides TNIK and/or MAP4K4 kinases inhibitors for the treatment of disease. In one aspect, disclosed herein are kinase inhibitors having a structure of Formula (A), (A*), (I), (IIA), or (IIB). Further described herein are pharmaceutical composition comprising these compounds and methods of using these compounds. In one aspect, disclosed herein are methods of treating a disease or condition by administering the kinases inhibitors described herein.

CROSS REFERENCE

This application is a continuation application of U.S. patentapplication Ser. No. 17/678,315, filed Feb. 23, 2022, which claims thebenefit of International Application No. PCT/CN2021/077706, filed Feb.24, 2021 and International Application No. PCT/CN2021/142622, filed Dec.29, 2021, each of which is hereby incorporated by reference in itsentirety.

BACKGROUND OF THE INVENTION

A biologically active enzyme known as Traf2- and Nck-interacting proteinkinase is an enzyme commonly known as the TNK in humans, and which isencoded by the TNIK gene TNIK as a serine/threonine kinase is involvedin various biological processes. There is a need for new drug candidatesthat can target TNIK.

SUMMARY OF THE INVENTION

TNIK is a serine/threonine kinase that is involved in various biologicalprocesses including acting as an essential regulatory component of theWnt signaling pathway. TNIK directly binds TCF4 and b-catenin andphosphorylates TCF4. Additionally, TNIK plays an activator of Wnt targetgene expression and modulates the actin cytoskeleton and activates thec-Jun N-terminal kinase pathway, which is responsive to stress. It isalso part of a signaling complex composed of NEDD4, RAP2A, and TNIK,which regulates neuronal dendrite extension and arbonization duringdevelopment. More generally, TNIK may play a role in cytoskeletalrearrangement and regulate cell spreading. TNIK also causes weak Smad1T322 phosphorylation, involved in TGF-b1 signaling transduction.

TNIK is considered to be a germinal center kinase (GCK), which can becharacterized by an N-terminal kinase domain and a C-terminal GCK domainthat serves a regulatory function.

TNIK activation of Wnt signaling plays important roles in carcinogenesisand embryonic development. Mutations in this gene are associated with anautosomal recessive form of cognitive disability.

Additionally, TNIK is linked to cancer, including for example,colorectal cancer. As such, TNIK has been identified as an attractivecandidate for drugs targeting certain cancers.

The current data imply TNIK is a potential target for the generation ofsmall molecule inhibitors to specifically block the Wnt pathway indisease states such as colorectal cancer or the autosomal recessive formof cognitive disability.

Also, it is known that TGF-β-activated EMT can be identified through theattenuation of Smad and non-Smad signaling pathways, including the Wnt,FF-kB, FAK-Src-paxillin-related focal adhesion, and MAP kinase (ERK andJNK) signaling pathways. As such, therapeutic targets associated withEMT, such as TNIK being target for inhibition, can be used for therapiesfor treating and/or preventing EMT-based disorders, such as cancermetastasis and fibrosis.

Accordingly, it would be advantageous to have a TNIK inhibitor that caninhibit the kinase activity of TNIK, as a member of the Ste20 family ofMAP kinase kinase kinase (MAP4K).

The present disclosure addresses the above need and provides additionaladvantages as well.

In some aspects, the present disclosure provides a compound representedby Formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

-   Z is selected from optionally substituted 3- to 12-membered    heterocycle and optionally substituted C₃-C₁₂ carbocycle, wherein    the substituents on each are independently selected at each    occurrence from one or more —N(R¹⁰)₂, halogen, —OH, —CN, —NO₂, —NH₂,    oxo, ═S, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀    alkynyl, C₁-C₁₀ alkyl, C₃₋₁₂ carbocycle, 3- to 12-membered    heterocycle;    -   wherein the C₁-C₁₀ alkyl is optionally substituted with one or        more substituents independently selected at each occurrence from        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀ haloalkyl,        —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl), C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered        heterocycle;    -   wherein the C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        are each optionally substituted at each occurrence from one or        more substituents independently selected from halogen, —OH, —CN,        —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀        alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to        12-membered heterocycle, and optionally substituted C₁₋₁₀ alkyl,        wherein the optional substituents on the C₁₋₁₀ alkyl are        independently selected at each occurrence from one or more        hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl, —NH₂, —CN, and —NO₂;-   R¹⁰ is selected from optionally substituted C₁-C₆ alkyl, wherein the    optional substituents on C₁-C₆ alkyl are independently selected at    each occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo,    ═S, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,    C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle;-   W is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl; and-   Y is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.

In some aspects, the disclosure provides a compound re resented byFormula (A*):

-   R¹ is selected from:    -   —N(R⁵)₂, wherein R⁵ is selected from hydrogen, and optionally        substituted C₁-C₆ alkyl, wherein the optional substituents on        C₁-C₆ alkyl are independently selected at each occurrence from        one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle;    -   optionally substituted C₁-C₆ alkyl, wherein the substituents on        C₁-C₆ alkyl are independently selected at each occurrence from        one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl),        C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to        12-membered heterocycle;    -   optionally substituted 3 to 8-membered heterocycle; wherein the        optional substituents on the 3 to 8-membered heterocycle are        independently selected at each occurrence from one or more        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle, and optionally        substituted C₁₋₁₀ alkyl, wherein the optional substituents on        the C₁₋₁₀ alkyl are independently selected at each occurrence        from one or more hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl, —NH₂,        —CN, and —NO₂;-   W is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl; and-   Y is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.

In certain embodiments, the disclosure provides a compound representedby Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from:    -   —N(R⁵)₂, wherein R⁵ is selected from hydrogen, and optionally        substituted C₁-C₆ alkyl, wherein the optional substituents on        C₁-C₆ alkyl are independently selected at each occurrence from        one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle;    -   substituted C₁-C₆ alkyl, wherein the substituents on C₁-C₆ alkyl        are independently selected at each occurrence from one or more        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀ haloalkyl,        —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl), C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered        heterocycle;    -   optionally substituted 3 to 8-membered heterocycle; wherein the        optional substituents on the 3 to 8-membered heterocycle are        independently selected at each occurrence from one or more        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle, and optionally        substituted C₁₋₁₀ alkyl, wherein the optional substituents on        the C₁₋₁₀ alkyl are independently selected at each occurrence        from one or more hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl, —NH₂,        —CN, and —NO₂;-   R³ is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle and optionally substituted    C₃₋₁₀ carbocycle, wherein the optional substituents on each are    independently selected at each occurrence from one or more halogen,    —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₆ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3-    to 12-membered heterocycle;-   R⁴ is selected from:    -   hydrogen;    -   optionally substituted C₁-C₆ alkyl, wherein the optional        substituents on C₁-C₆ alkyl are independently selected at each        occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo,        ═S, —O—C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered        heterocycle;    -   optionally substituted C₃₋₁₀ carbocycle, wherein the optional        substituents on C₃₋₁₀ carbocycle are independently selected at        each occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂,        oxo, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered        heterocycle; and-   W is selected from optionally substituted 5- to 8-membered    heteroaryl, wherein the substituents on the optionally substituted    5- to 8-membered heteroaryl are independently selected at each    occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S,    —S(O₂)NH₂, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀    alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle.

In some aspects, the disclosure provides a pharmaceutical compositioncomprising a compound or salt of Formula (A), Formula (A*), or Formula(I) and a pharmaceutically acceptable excipient.

In some aspects, the disclosure provides a method of treating orpreventing disease comprising administering a compound or salt ofFormula (A), Formula (A*), or Formula (I) or a pharmaceuticalcomposition comprising a compound or salt of Formula (A), Formula (A*),or Formula (I) and a pharmaceutically acceptable excipient to a subjectin need thereof. In some aspects, the disease is a cancer. In somecases, the cancer is selected from colorectal cancer, gastric cancer,breast cancer, lung cancer, pancreatic cancer, prostate cancer, multiplemyeloma, chronic myelogenous leukemia, cancer metastasis, fibrosis andpsychiatric disorders. In some cases, the pharmaceutical composition canbe used as an inhibitor of tumor immunosuppression in combination withchemotherapy or immune checkpoint inhibitor therapy for cancer. In somecases, the pharmaceutical composition can be used to treat a fibroticdisease or condition including but not limited to chronic kidneyfibrosis (“CKD”), liver cirrhosis, pulmonary fibrosis, renalinterstitial fibrosis, myocardial infarction, skin fibrosis, systemicsclerosis (“SSc”), and graft-versus-host disease (“GVHD”). In somecases, the pharmaceutical composition can be used to treat kidneyfibrosis. In some cases, the pharmaceutical composition can be used totreat skin fibrosis. In some cases, the pharmaceutical composition canbe used to treat idiopathic pulmonary fibrosis (IPF). In some cases, thepharmaceutical composition can be used to treat a disease is associatedwith TNIK kinase.

In some aspects, the disclosure provides a method of inhibiting TNIKkinase comprising administering a compound or salt of Formula (A),Formula (A*), or Formula (I) or a pharmaceutical composition comprisinga compound or salt of Formula (A), Formula (A*), or Formula (I) and apharmaceutically acceptable excipient to a subject in need thereof.

In some aspects, the disclosure provides a method of inhibiting MAP4K4kinase comprising administering a compound or salt of Formula (A),Formula (A*), or Formula (I) or a pharmaceutical composition comprisinga compound or salt of Formula (A), Formula (A*), or Formula (I) and apharmaceutically acceptable excipient to a subject in need thereof.

Additional aspects and advantages of the present disclosure will becomereadily apparent to those skilled in this art from the followingdetailed description, wherein only illustrative embodiments of thepresent disclosure are shown and described. As will be realized, thepresent disclosure is capable of other and different embodiments, andits several details are capable of modifications in various obviousrespects, all without departing from the disclosure. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.To the extent publications and patents or patent applicationsincorporated by reference contradict the disclosure contained in thespecification, the specification is intended to supersede and/or takeprecedence over any such contradictory material.

DETAILED DESCRIPTION OF THE INVENTION

While various embodiments of the invention have been shown and describedherein, it will be obvious to those skilled in the art that suchembodiments are provided by way of example only.

Numerous variations, changes, and substitutions may occur to thoseskilled in the art without departing from the invention. It should beunderstood that various alternatives to the embodiments of the inventiondescribed herein may be employed.

A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, and preferably having from one to fifteen carbon atoms(i.e., C₁-C₁₅ alkyl). In certain embodiments, an alkyl comprises one tothirteen carbon atoms (i.e., C₁-C₁₃ alkyl). In certain embodiments, analkyl comprises one to eight carbon atoms (i.e., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (i.e., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (i.e., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (i.e., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (i.e., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (i.e., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(i.e., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (i.e., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (i.e., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (i.e., C₃-C₅alkyl). In certain embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group may beoptionally substituted, for example, with oxo, halogen, amino, nitrile,nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

In some embodiments, the alkyl is optionally substituted with oxo,halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the alkyl is optionally substituted with halogen, —CN, —OH,or —OMe. In some embodiments, the alkyl is optionally substituted withhalogen.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas alkyl, alkenyl, or alkynyl is meant to include groups that containfrom x to y carbons in the chain. For example, the term “C₁₋₆alkyl”refers to an alkyl group that may consist of 1 carbon atom, 2 carbonatoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms,including straight-chain alkyl and branched-chain alkyl groups.

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above. Unlessstated otherwise specifically in the specification, an alkoxy group maybe optionally substituted, for example, with oxo, halogen, amino,nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate,aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, the alkoxy is optionally substituted with halogen, —CN,—COOH, COOMe, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, the alkoxyis optionally substituted with halogen, —CN, —OH, or —OMe. In someembodiments, the alkoxy is optionally substituted with halogen.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and preferably having from two totwelve carbon atoms (i.e., C₂-C₁₂ alkenyl). In certain embodiments, analkenyl comprises two to eight carbon atoms (i.e., C₂-C₈ alkenyl). Incertain embodiments, an alkenyl comprises two to six carbon atoms (i.e.,C₂-C₆ alkenyl). In other embodiments, an alkenyl comprises two to fourcarbon atoms (i.e., C₂-C₄ alkenyl). The alkenyl is attached to the restof the molecule by a single bond, for example, ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl,and the like. Unless stated otherwise specifically in the specification,an alkenyl group may be optionally substituted, for example, with oxo,halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl,carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and thelike. In some embodiments, the alkenyl is optionally substituted withoxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the alkenyl is optionally substituted with halogen, —CN,—OH, or —OMe. In some embodiments, the alkenyl is optionally substitutedwith halogen.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, and preferably having from two totwelve carbon atoms (i.e., C₂-C₁₂ alkynyl). In certain embodiments, analkynyl comprises two to eight carbon atoms (i.e., C₂-C₈ alkynyl). Inother embodiments, an alkynyl comprises two to six carbon atoms (i.e.,C₂-C₆ alkynyl). In other embodiments, an alkynyl comprises two to fourcarbon atoms (i.e., C₂-C₄ alkynyl). The alkynyl is attached to the restof the molecule by a single bond, for example, ethynyl, propynyl,butynyl, pentynyl, hexynyl, and the like. Unless stated otherwisespecifically in the specification, an alkynyl group may be optionallysubstituted, for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, thealkynyl is optionally substituted with oxo, halogen, —CN, —COOH, COOMe,—OH, —OMe, —NH₂, or —NO₂. In some embodiments, the alkynyl is optionallysubstituted with halogen, —CN, —OH, or —OMe. In some embodiments, thealkynyl is optionally substituted with halogen.

The terms “C_(x-y)alkenyl” and “C_(x-y)alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond, respectively. The term—C_(x-y)alkenylene-refers to a substituted or unsubstituted alkenylenechain with from x to y carbons in the alkenylene chain. For example,—C₂₋₆alkenylene-may be selected from ethenylene, propenylene,butenylene, pentenylene, and hexenylene, any one of which is optionallysubstituted. An alkenylene chain may have one double bond or more thanone double bond in the alkenylene chain. The term —C_(x-y)alkynylene-refers to a substituted or unsubstituted alkynylene chain with from x toy carbons in the alkenylene chain.

For example, —C₂₋₆alkenylene- may be selected from ethynylene,propynylene, butynylene, pentynylene, and hexynylene, any one of whichis optionally substituted. An alkynylene chain may have one triple bondor more than one triple bond in the alkynylene chain.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation,and preferably having from one to twelve carbon atoms, for example,methylene, ethylene, propylene, n-butylene, and the like. The alkylenechain is attached to the rest of the molecule through a single bond andto the radical group through a single bond. The points of attachment ofthe alkylene chain to the rest of the molecule and to the radical groupmay be through any two carbons within the chain. In certain embodiments,an alkylene comprises one to ten carbon atoms (i.e., C₁-C₈ alkylene). Incertain embodiments, an alkylene comprises one to eight carbon atoms(i.e., C₁-C₈ alkylene). In other embodiments, an alkylene comprises oneto five carbon atoms (i.e., C₁-C₅ alkylene). In other embodiments, analkylene comprises one to four carbon atoms (i.e., C₁-C₄ alkylene). Inother embodiments, an alkylene comprises one to three carbon atoms(i.e., C₁-C₃ alkylene). In other embodiments, an alkylene comprises oneto two carbon atoms (i.e., C₁-C₂ alkylene). In other embodiments, analkylene comprises one carbon atom (i.e., C₁ alkylene). In otherembodiments, an alkylene comprises five to eight carbon atoms (i.e.,C₅-C₈ alkylene). In other embodiments, an alkylene comprises two to fivecarbon atoms (i.e., C₂-C₅ alkylene). In other embodiments, an alkylenecomprises three to five carbon atoms (i.e., C₃-C₅ alkylene). The term—C_(x-y)alkylene- refers to a substituted or unsubstituted alkylenechain with from x to y carbons in the alkylene chain. For example—C₁₋₆alkylene- may be selected from methylene, ethylene, propylene,butylene, pentylene, and hexylene, any one of which is optionallysubstituted.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon double bond, and preferably having from two to twelvecarbon atoms. The alkenylene chain is attached to the rest of themolecule through a single bond and to the radical group through a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group may be through any two carbonswithin the chain. In certain embodiments, an alkenylene comprises two toten carbon atoms (i.e., C₂-C₁₀ alkenylene). In certain embodiments, analkenylene comprises two to eight carbon atoms (i.e., C₂-C₈ alkenylene).In other embodiments, an alkenylene comprises two to five carbon atoms(i.e., C₂-C₅ alkenylene). In other embodiments, an alkenylene comprisestwo to four carbon atoms (i.e., C₂-C₄ alkenylene). In other embodiments,an alkenylene comprises two to three carbon atoms (i.e., C₂-C₃alkenylene). In other embodiments, an alkenylene comprises two carbonatom (i.e., C₂ alkenylene). In other embodiments, an alkenylenecomprises five to eight carbon atoms (i.e., C₅-C₈ alkenylene). In otherembodiments, an alkenylene comprises three to five carbon atoms (i.e.,C₃-C₅ alkenylene).

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon triple bond, and preferably having from two to twelvecarbon atoms. The alkynylene chain is attached to the rest of themolecule through a single bond and to the radical group through a singlebond. The points of attachment of the alkynylene chain to the rest ofthe molecule and to the radical group may be through any two carbonswithin the chain. In certain embodiments, an alkynylene comprises two toten carbon atoms (i.e., C₂-C₁₀ alkynylene). In certain embodiments, analkynylene comprises two to eight carbon atoms (i.e., C₂-C₈ alkynylene).In other embodiments, an alkynylene comprises two to five carbon atoms(i.e., C₂-C₅ alkynylene). In other embodiments, an alkynylene comprisestwo to four carbon atoms (i.e., C₂-C₄ alkynylene). In other embodiments,an alkynylene comprises two to three carbon atoms (i.e., C₂-C₃alkynylene). In other embodiments, an alkynylene comprises two carbonatom (i.e., C₂ alkynylene). In other embodiments, an alkynylenecomprises five to eight carbon atoms (i.e., C₅-C₈ alkynylene). In otherembodiments, an alkynylene comprises three to five carbon atoms (i.e.,C₃-C₅ alkynylene).

“Aryl” refers to a radical derived from an aromatic monocyclic oraromatic multicyclic hydrocarbon ring system by removing a hydrogen atomfrom a ring carbon atom, wherein the ring system contains at least onearomatic ring. The aromatic monocyclic or aromatic multicyclichydrocarbon ring system contains only hydrogen and carbon and from fiveto eighteen carbon atoms, where at least one of the rings in the ringsystem is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. The aryl radical may be a monocyclic, bicyclic, tricyclicor tetracyclic ring system, which may include fused or bridged ringsystems. In some embodiments, the aryl is a 6- to 10-membered aryl. Insome embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicalsinclude, but are not limited to, aryl radicals derived from thehydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. Unless statedotherwise specifically in the specification, an aryl may be optionallysubstituted, for example, with halogen, amino, nitrile, nitro, hydroxyl,alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, the aryl is optionally substituted with halogen, methyl,ethyl, —CN, —COOH, COOMe, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the aryl is optionally substituted with halogen, methyl,ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, the aryl isoptionally substituted with halogen.

“Heteroalkyl” refers to an alkyl group in which one or more skeletalatoms of the alkyl are selected from an atom other than carbon, e.g.,oxygen, nitrogen (e.g., —NH—, —N(alkyl)-), sulfur, phosphorus, orcombinations thereof. A heteroalkyl is attached to the rest of themolecule at a carbon atom of the heteroalkyl. In one aspect, aheteroalkyl is a C₁-C₆ heteroalkyl wherein the heteroalkyl is comprisedof 1 to 6 carbon atoms and one or more atoms other than carbon, e.g.,oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, phosphorus, orcombinations thereof wherein the heteroalkyl is attached to the rest ofthe molecule at a carbon atom of the heteroalkyl. Examples of suchheteroalkyl are, for example, —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₂OCH₃,—CH(CH₃)OCH₃, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂CH₂NHCH₃, or —CH₂CH₂N(CH₃)₂.Unless stated otherwise specifically in the specification, a heteroalkylis optionally substituted for example, with oxo, halogen, amino,nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy,aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, a heteroalkyl is optionally substituted with oxo, halogen,methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments,a heteroalkyl is optionally substituted with oxo, halogen, methyl,ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, the heteroalkyl isoptionally substituted with halogen.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. “Aralkynyl” refers to a radicalof the formula —R^(c)-aryl, where Re is an alkynylene chain as definedabove.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring systemin which each ring atom of the ring system is carbon. Carbocycle mayinclude 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclicrings, and 6- to 12-membered bridged rings. Each ring of a bicycliccarbocycle may be selected from saturated, unsaturated, and aromaticrings. An aromatic ring, e.g., phenyl, may be fused to a saturated orunsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Anycombination of saturated, unsaturated and aromatic bicyclic rings, asvalence permits, are included in the definition of carbocyclic.Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl,adamantyl, phenyl, indanyl, and naphthyl. In some embodiments, thecarbocycle is an aryl. In some embodiments, the carbocycle is acycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. Insome embodiments, the carbocycle contains a triple bond. Unless statedotherwise specifically in the specification, a carbocycle can beoptionally substituted.

“Cycloalkyl” refers to a fully saturated monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, and preferably having fromthree to twelve carbon atoms. In certain embodiments, a cycloalkylcomprises three to ten carbon atoms. In other embodiments, a cycloalkylcomprises five to seven carbon atoms. The cycloalkyl may be attached tothe rest of the molecule by a single bond. Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicalsinclude, for example, adamantyl, norbornyl (i.e.,bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless statedotherwise specifically in the specification, a cycloalkyl is optionallysubstituted, for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl,carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and thelike.

In some embodiments, a cycloalkyl is optionally substituted with oxo,halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF₃, —OH, —OMe, —NH₂, or—NO₂. In some embodiments, a cycloalkyl is optionally substituted withoxo, halogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In someembodiments, the cycloalkyl is optionally substituted with halogen.

“Heterocycloalkyl” refers to a cycloalkyl group, as defined above,wherein one or more ring carbons are replaced with one or moreheteroatoms, such as N, O, P, and S. A heterocycloalkyl may beoptionally substituted.

“Cycloalkenyl” refers to an unsaturated non-aromatic monocyclic orpolycyclic hydrocarbon radical consisting solely of carbon and hydrogenatoms, which includes fused or bridged ring systems, preferably havingfrom three to twelve carbon atoms and comprising at least one doublebond. In certain embodiments, a cycloalkenyl comprises one double bond.In certain embodiments, a cycloalkenyl comprises more than one doublebond. In certain embodiments, a cycloalkenyl comprises three to tencarbon atoms. In other embodiments, a cycloalkenyl comprises five toseven carbon atoms. The cycloalkenyl may be attached to the rest of themolecule by a single bond.

Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl,cyclohexenyl, cycloheptenyl, and cyclooctenyl.

“Heterocycloalkenyl” refers to a cycloalkenyl group, as defined above,wherein one or more ring carbons are replaced with one or moreheteroatoms, such as N, O, P, and S. A heterocycloalkenyl may beoptionally substituted.

“Cycloalkylalkyl” refers to a radical of the formula —R^(c)-cycloalkylwhere R^(c) is an alkylene chain as described above.

“Cycloalkylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-cycloalkyl where R^(c) is an alkylene chain asdescribed above.

“Halo” or “halogen” refers to halogen substituents such as bromo,chloro, fluoro and iodo substituents.

As used herein, the term “haloalkyl” or “haloalkane” refers to an alkylradical, as defined above, that is substituted by one or more halogenradicals, for example, trifluoromethyl, dichloromethyl, bromomethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Insome embodiments, the alkyl part of the fluoroalkyl radical isoptionally further substituted.

Examples of halogen substituted alkanes (“haloalkanes”) includehalomethane (e.g., chloromethane, bromomethane, fluoromethane,iodomethane), di- and trihalomethane (e.g., trichloromethane,tribromomethane, trifluoromethane, triiodomethane), 1-haloethane,2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane,3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane,1,2,3-trihalopropane, and any other suitable combinations of alkanes (orsubstituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When analkyl group is substituted with more than one halogen radicals, eachhalogen may be independently selected e.g., 1-chloro, 2-fluoroethane.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, for example,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like.

“Heterocycle” refers to a saturated, unsaturated or aromatic ringcomprising one or more heteroatoms. Exemplary heteroatoms include N, O,Si, P, B, and S atoms. Heterocycles include e.g., 3- to 10-memberedmonocyclic rings, 6- to 12-membered bicyclic rings, and 6- to12-membered bridged rings. Each ring of a bicyclic heterocycle may beselected from saturated, unsaturated, and aromatic rings.“Heterocyclene” refers to a divalent heterocycle linking the rest of themolecule to a radical group. Unless stated otherwise specifically in thespecification, a heterocycle is optionally substituted, for example,with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl,alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, theheterocycle is optionally substituted with halogen, methyl, ethyl, —CN,—CF₃, —OH, or —OMe. In some embodiments, the heterocycloalkyl isoptionally substituted with halogen. In some embodiments, a heterocycleis a heteroaryl. In some embodiments, a heterocycle is aheterocycloalkyl. In some embodiments, a heterocycle is aheterocycloalkenyl. In some embodiments, a heterocycle contains one ormore triple bonds.

In some embodiments, the heterocycle comprises one to three heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur. Insome embodiments, the heterocycle comprises one to three heteroatomsselected from the group consisting of nitrogen and oxygen. In someembodiments, the heterocycle comprises one to three nitrogens. In someembodiments, the heterocycle comprises one or two nitrogens. In someembodiments, the heterocycle comprises one nitrogen. In someembodiments, the heterocycle comprises one nitrogen and one oxygen.Unless stated otherwise specifically in the specification, theheterocycle radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused, spiro, or bridged ringsystems; and the nitrogen, carbon, or sulfur atoms in the heterocycleradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Representative heterocycles include, the heteroaryl groupsdescribed below. Representative heterocycle also include, but are notlimited to, heterocycles having from two to fifteen carbon atoms (C₂-C₁₅heterocycloalkyl or C₂-C₁₅ heterocycloalkenyl), from two to ten carbonatoms (C₂-C₁₀ heterocycloalkyl or C₂-C₁₀ heterocycloalkenyl), from twoto eight carbon atoms (C₂-C₈ heterocycloalkyl or C₂-C₈heterocycloalkenyl), from two to seven carbon atoms (C₂-C₇heterocycloalkyl or C₂-C₇ heterocycloalkenyl), from two to six carbonatoms (C₂-C₆ heterocycloalkyl or C₂-C₇ heterocycloalkenyl), from two tofive carbon atoms (C₂-C₅ heterocycloalkyl or C₂-C₅ heterocycloalkenyl),or two to four carbon atoms (C₂-C₄ heterocycloalkyl or C₂-C₄heterocycloalkenyl). Examples of such heterocycle radicals include, butare not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl,3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and2-oxo-1,3-dioxol-4-yl. The term heterocycle also includes all ring formsof the carbohydrates, including but not limited to the monosaccharides,the disaccharides and the oligosaccharides. In some embodiments,heterocycles have from 2 to 10 carbons in the ring. It is understoodthat when referring to the number of carbon atoms in a heterocycle, thenumber of carbon atoms in the heterocycle is not the same as the totalnumber of atoms (including the heteroatoms) that make up the heterocycle(i.e. skeletal atoms of the heterocycle ring). In some embodiments, theheterocycle is a 3- to 8-membered. In some embodiments, the heterocycleis a 3 to 7-membered. In some embodiments, the heterocycle is a 3- to6-membered. In some embodiments, the heterocycle is a 4- to 6-membered.In some embodiments, the heterocycle is a 5 to 6-membered.

“Heteroaryl” or “aromatic heterocycle” refers to a radical derived froma heteroaromatic ring radical that comprises one to thirteen carbonatoms, at least one heteroatom wherein each heteroatom may be selectedfrom N, O, and S, and at least one aromatic ring. As used herein, theheteroaryl ring may be selected from monocyclic or bicyclic and fused orbridged ring systems rings wherein at least one of the rings in the ringsystem is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. Theheteroatom(s) in the heteroaryl radical may be optionally oxidized. Oneor more nitrogen atoms, if present, are optionally quaternized. Theheteroaryl may be attached to the rest of the molecule through any atomof the heteroaryl, valence permitting, such as a carbon or nitrogen atomof the heteroaryl. Examples of heteroaryls include, but are not limitedto, pyridine, pyrimidine, oxazole, furan, thiophene, benzthiazole, andimdazopyridine. An “X-membered heteroaryl” refers to the number ofendocylic atoms, i.e., X, in the ring. For example, a 5-memberedheteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclicatoms, e.g., triazole, oxazole, thiophene, etc. In some embodiments, theheteroaryl is a 5 to 10-membered heteroaryl. In some embodiments, theheteroaryl is a 5- to 6-membered heteroaryl.

In some embodiments, the heteroaryl is a 6-membered heteroaryl. In someembodiments, the heteroaryl is a 5-membered heteroaryl. Examplesinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl,benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl,1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl,quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl,thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, andthiophenyl (i.e., thienyl). Unless stated otherwise specifically in thespecification, a heteroaryl may be optionally substituted, for example,with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, theheteroaryl is optionally substituted with halogen, methyl, ethyl, —CN,—COOH, COOMe, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, theheteroaryl is optionally substituted with halogen, methyl, ethyl, —CN,—CF₃, —OH, or —OMe. In some embodiments, the heteroaryl is optionallysubstituted with halogen.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons or substitutable heteroatoms, e.g.,NH, of the structure. It will be understood that “substitution” or“substituted with” includes the implicit proviso that such substitutionis in accordance with permitted valence of the substituted atom and thesubstituent, and that the substitution results in a stable compound,i.e., a compound which does not spontaneously undergo transformationsuch as by rearrangement, cyclization, elimination, etc. In certainembodiments, substituted refers to moieties having substituentsreplacing two hydrogen atoms on the same carbon atom, such assubstituting the two hydrogen atoms on a single carbon with an oxo,imino or thioxo group. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds. For purposes of thisdisclosure, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valences of the heteroatoms.

In some embodiments, substituents may include any substituents describedherein, for example: halogen, hydroxy, oxo (═O), thioxo (═S), cyano(—CN), nitro (—NO₂), imino (═N—H), oximo (═N—OH), hydrazino (═N—NH₂),—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); and alkyl, alkenyl,alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,cycloalkylalkyl, and heterocycle, any of which may be optionallysubstituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl,haloalkynyl, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino(═N—H), oximo (═N—OH), hydrazine (═N—NH₂), —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); wherein each R^(a) isindependently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each R^(a),valence permitting, may be optionally substituted with alkyl, alkenyl,alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (═O), thioxo(═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo (═N—OH), hydrazine(═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); and wherein each R^(b) isindependently selected from a direct bond or a straight or branchedalkylene, alkenylene, or alkynylene chain, and each R^(c) is a straightor branched alkylene, alkenylene or alkynylene chain.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

The term “salt” or “pharmaceutically acceptable salt” refers to saltsderived from a variety of organic and inorganic counter ions well knownin the art. Pharmaceutically acceptable acid addition salts can beformed with inorganic acids and organic acids. Inorganic acids fromwhich salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Organic bases from which salts can be derivedinclude, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like, specificallysuch as isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In some embodiments, thepharmaceutically acceptable base addition salt is chosen from ammonium,potassium, sodium, calcium, and magnesium salts.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion,

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable excipient” or “pharmaceuticallyacceptable carrier” as used herein means a pharmaceutically acceptablematerial, composition or vehicle, such as a liquid or solid filler,diluent, excipient, solvent or encapsulating material. Each carrier mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not injurious to the patient. Someexamples of materials which can serve as pharmaceutically acceptablecarriers include: (1) sugars, such as lactose, glucose and sucrose; (2)starches, such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)tale; (8) excipients, such as cocoa butter and suppository waxes; (9)oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar; (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

In certain embodiments, the term “prevent” or “preventing” as related toa disease or disorder may refer to a compound that, in a statisticalsample, reduces the occurrence of the disorder or condition in thetreated sample relative to an untreated control sample, or delays theonset or reduces the severity of one or more symptoms of the disorder orcondition relative to the untreated control sample.

The terms “treat,” “treating” or “treatment,” as used herein, mayinclude alleviating, abating or ameliorating a disease or conditionsymptoms, preventing additional symptoms, ameliorating or preventing theunderlying causes of symptoms, inhibiting the disease or condition,e.g., arresting the development of the disease or condition, relievingthe disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

B. Compounds of the Disclosure

In certain embodiments, the disclosure provides a compound representedby Formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

-   Z is selected from optionally substituted 3- to 12-membered    heterocycle and optionally substituted C₃-C₁₂ carbocycle, wherein    the substituents on each are independently selected at each    occurrence from one or more —N(R¹⁰)₂, halogen, —OH, —CN, —NO₂, —NH₂,    oxo, ═S, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀    alkynyl, C₁-C₁₀ alkyl, C₃₋₁₂ carbocycle, 3- to 12-membered    heterocycle;    -   wherein the C₁-C₁₀ alkyl is optionally substituted with one or        more substituents independently selected at each occurrence from        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀ haloalkyl,        —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl), C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered        heterocycle;    -   wherein the C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        are each optionally substituted at each occurrence from one or        more substituents independently selected from halogen, —OH, —CN,        —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀        alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to        12-membered heterocycle, and optionally substituted C₁₋₁₀ alkyl,        wherein the optional substituents on the C₁₋₁₀ alkyl are        independently selected at each occurrence from one or more        hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl, —NH₂, —CN, and —NO₂;-   R¹⁰ is selected from optionally substituted C₁-C₆ alkyl, wherein the    optional substituents on C₁-C₆ alkyl are independently selected at    each occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo,    ═S, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,    C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle;-   W is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl; and-   Y is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.

In some aspects, the compound of Formula (A) is represented by Formula(A*).

In some embodiments, for a compound or salt of Formula (A), Z isselected from optionally substituted 3- to 12-membered heterocycle andoptionally substituted C₃-C₁₂ carbocycle, wherein the substituents oneach are independently selected at each occurrence from one or morehalogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀alkyl. In some cases, for Z, the heterocycle includes at least onenitrogen atom. In some cases, Z is selected from optionally substitutedphenyl and optionally substituted pyridine. In some cases, the optionalsubstituents of the optionally substituted phenyl of Z are selected fromone or more substituents selected from halogen, —OH, —CN, —NO₂, —NH₂,oxo, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl. In somecases, the optional substituents of the optionally substituted phenyl ofZ are selected from one or more substituents selected from halogen andC₁₋₁₀ alkyl. In some cases, the heterocycle is unsubstituted. In somecases, Z is selected from substituted phenyl and unsubstituted pyridine.In some cases, the heterocycle has 1 or 2 nitrogen atoms. In some cases,the heterocycle has only 1 nitrogen atom. In some cases, the heterocyclehas only 2 nitrogen atoms. In some cases, the heterocycle is a6-membered heterocycle.

In some cases, Z is selected from

In some cases, the optional substituents of the optionally substitutedphenyl of Z is halogen. In some cases, Z is selected from

In some cases, Z is substituted phenyl. In some cases, Z is phenylsubstituted with halogen.

In some aspects, the disclosure provides a compound represented byFormula (A*):

-   R¹ is selected from:    -   —N(R⁵)₂, wherein R⁵ is selected from hydrogen, and optionally        substituted C₁-C₆ alkyl, wherein the optional substituents on        C₁-C₆ alkyl are independently selected at each occurrence from        one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle;    -   optionally substituted C₁-C₆ alkyl, wherein the substituents on        C₁-C₆ alkyl are independently selected at each occurrence from        one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl),        C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to        12-membered heterocycle;    -   optionally substituted 3 to 8-membered heterocycle; wherein the        optional substituents on the 3 to 8-membered heterocycle are        independently selected at each occurrence from one or more        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle, and optionally        substituted C₁₋₁₀ alkyl, wherein the optional substituents on        the C₁₋₁₀ alkyl are independently selected at each occurrence        from one or more hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl, —NH₂,        —CN, and —NO₂;-   W is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl; and-   Y is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.

In some aspects, the compound of Formula (A) or Formula (A*) arerepresented by Formula (I).

In some aspects, the disclosure provides a compound represented byFormula (A*):

-   R¹ is selected from:    -   —N(R⁵)₂, wherein R⁵ is selected from hydrogen, and optionally        substituted C₁-C₆ alkyl, wherein the optional substituents on        C₁-C₆ alkyl are independently selected at each occurrence from        one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle;    -   optionally substituted C₁-C₆ alkyl, wherein the substituents on        C₁-C₆ alkyl are independently selected at each occurrence from        one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl),        C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to        12-membered heterocycle;    -   optionally substituted 3 to 14-membered heterocycle; wherein the        optional substituents on the 3 to 8-membered heterocycle are        independently selected at each occurrence from one or more        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀        heteroalkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,        C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle,        and optionally substituted C₁₋₁₀ alkyl, wherein the optional        substituents on the C₁₋₁₀ alkyl are independently selected at        each occurrence from one or more hydroxy, halogen, oxo, —C₁₋₁₀        haloalkyl, —NH₂, —CN, and —NO₂;-   W is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl; and-   Y is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.

In some aspects, the disclosure provides a compound represented byFormula (A*):

-   R¹ is selected from:    -   —N(R⁵)₂, wherein R⁵ is selected from hydrogen and optionally        substituted C₁-C₆ alkyl; optionally substituted C₁-C₆ alkyl;    -   optionally substituted 3 to 14-membered heterocycle or        optionally substituted 3 to 14-membered carbocycle;-   W is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle;    -   and Y is selected from optionally substituted 5- to 8-membered        heterocycle and optionally substituted C₃-C₈ carbocycle.

In some embodiments, R is optionally substituted 3 to 14-memberedheterocycle.

In certain embodiments, the disclosure provides a compound representedby Formula (I):

-   -   or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from:    -   —N(R⁵)₂, wherein R⁵ is selected from hydrogen, and optionally        substituted C₁-C₆ alkyl, wherein the optional substituents on        C₁-C₆ alkyl are independently selected at each occurrence from        one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle;    -   substituted C₁-C₆ alkyl, wherein the substituents on C₁-C₆ alkyl        are independently selected at each occurrence from one or more        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀ haloalkyl,        —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl), C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered        heterocycle;    -   optionally substituted 3 to 8-membered heterocycle; wherein the        optional substituents on the 3 to 8-membered heterocycle are        independently selected at each occurrence from one or more        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle, and optionally        substituted C₁₋₁₀ alkyl, wherein the optional substituents on        the C₁₋₁₀ alkyl are independently selected at each occurrence        from one or more hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl, —NH₂,        —CN, and —NO₂;

-   R³ is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle and optionally substituted    C₃₋₁₀ carbocycle, wherein the optional substituents on each are    independently selected at each occurrence from one or more halogen,    —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₆ alkyl, —C₁₋₁₀ haloalkyl,    —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3 to    12-membered heterocycle;

-   R⁴ is selected from:    -   hydrogen;    -   optionally substituted C₁-C₆ alkyl, wherein the optional        substituents on C₁-C₆ alkyl are independently selected at each        occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo,        ═S, —O—C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered        heterocycle;    -   optionally substituted C₃₋₁₀ carbocycle, wherein the optional        substituents on C₃₋₁₀ carbocycle are independently selected at        each occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂,        oxo, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered        heterocycle; and

-   W is selected from optionally substituted 5- to 8-membered    heteroaryl, wherein the substituents on the optionally substituted    5- to 8-membered heteroaryl are independently selected at each    occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S,    —S(O₂)NH₂, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀    alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle.

In certain embodiments, the disclosure provides a compound representedby Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from:    -   —N(R⁵)₂, wherein R⁵ is selected from hydrogen and optionally        substituted C₁-C₆ alkyl; substituted C₁-C₆ alkyl; and optionally        substituted 3 to 14-membered heterocycle (such as 5-6 membered        heterocycloalkyl);-   R³ is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle and optionally substituted    C₃₋₁₀ carbocycle;-   R⁴ is selected from:    -   hydrogen;    -   optionally substituted C₁-C₆ alkyl or optionally substituted        C₁-C₆ heteroalkyl; optionally substituted C₃₋₁₀ carbocycle or        optionally substituted 3- to 12-membered heterocycle; and        W is selected from optionally substituted 5- to 8-membered        heteroaryl (such as 5-6 membered heteroaryl).

In some embodiments, R⁴ is optionally substituted C₁-C₆ alkyl. In someembodiments, R⁴ is optionally substituted C₃₋₁₀ carbocycle.

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), when R¹ is methylpiperazine and W is pyridine, R⁴ is not methyl. Insome cases, when R¹ is

and W is pyridine, R⁴ is not methyl.

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), when W is furan, R⁴ is not ethan-1-one. In some cases, when W isfuran and R⁴ is cyclopentyl or cyclohexyl, R¹ is not ethan-1-one. Insome cases, when W is furan and R⁴ is cyclopentyl or cyclohexyl, R¹ isnot ethan-1-one. In some cases, R¹ is not

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), W is selected from optionally substituted 5- to 8-memberedheterocycle. In some cases, the heterocycle of W is a 5- to 8-memberedheteroaryl. In some cases, the heterocycle of W is an unsubstituted 5-to 8-membered heteroaryl. In some cases, the heterocycle of W is anunsubstituted 5-membered heteroaryl. In some cases, the heterocycle of Whas at least 2 heteroatoms. In some cases, the heterocycle of W has atmost 2 heteroatoms. In some cases, the heterocycle of W has only 2heteroatoms. In some cases, the heterocycle of W is unsubstituted. Insome cases, the heterocycle of W has 2 heteroatoms selected fromnitrogen, sulfur, and oxygen. In some cases, the heterocycle of W has atleast 2 different heteroatoms. In some cases, the heterocycle of W has 2nitrogen atoms. In some cases, the heterocycle of W has 1 nitrogen atomand 1 oxygen atom.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is optionally substituted. In some embodiments, R¹is optionally substituted with 1 to 4 substituents. In some embodiments,R¹ is optionally substituted with 1 to 3 substituents. In someembodiments, R¹ is optionally substituted with 1 to 2 substituents. Insome embodiments, R¹ is optionally substituted with 1 substituent. Insome embodiments, R¹ is optionally substituted with 2 substituents. Insome embodiments, R¹ is optionally substituted with 3 substituents. Insome embodiments, R¹ is monocyclic. In some embodiments, R¹ is bicyclic.In some embodiments, R¹ is a bridged ring. In some embodiments, R¹ is afused ring. In some embodiments, R¹ is a spiro ring. In someembodiments, R¹ is optionally substituted 3-12 membered ring. In someembodiments, R¹ is optionally substituted 5-8 membered ring.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is optionally substituted with an oxide.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from substituted C₁-C₆ alkyl, whereinthe substituents on C₁-C₆ alkyl are independently selected at eachoccurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, ═S, —C₁₋₁₀haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl), C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle. In some embodiments, for a compound or salt of Formula (A),(A*), (I), (IIA), or (IIB), R¹ is selected from substituted C₁-C₆ alkyl,wherein the substituents on C₁-C₆ alkyl are independently selected ateach occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, ═S,—C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₆alkyl), C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ carbocycle, and 3- to 12-memberedheterocycle. In some embodiments, R¹ is optionally substituted C₁-C₃alkyl. In some embodiments, R¹ is optionally substituted with one ormore substituents selected from oxo, halogen, —O—C₁₋₁₀ alkyl, —C₁₋₁₀haloalkyl, and —OH.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is optionally substituted C₁-C₁₀ heteroalkyl. Insome embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is optionally substituted C₁-C₆ heteroalkyl whereinthe substituents on C₁-C₆ heteroalkyl are independently selected at eachoccurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, ═S, —C₁₋₁₀haloalkyl, —C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle. In some embodiments, for a compound or salt ofFormula (A), (A*), (I), (IIA), or (IIB), R¹ is optionally substitutedC₁-C₆ heteroalkyl wherein the substituents on C₁-C₆ heteroalkyl areindependently selected at each occurrence from one or more halogen, —OH,—CN, —NO₂, —NH₂, ═S, —C₁₋₃ haloalkyl, —C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆carbocycle, and 3- to 12-membered heterocycle.

In some cases, when W is furan, R¹ is selected from substituted C₁-C₆alkyl, wherein the substituents on C₁-C₆ alkyl are independentlyselected at each occurrence from one or more halogen, —OH, —CN, —NO₂,—NH₂, oxo, ═S, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl,—O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from —N(R⁵)₂, In some embodiments, for acompound or salt of Formula (A), (A*), (I), (IIA), or (IIB), R¹ isselected from —N(R⁵)₂, wherein R⁵ is selected from optionallysubstituted C₁-C₆ alkyl, wherein the optional substituents on C₁-C₆alkyl are selected from hydroxy.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from substituted C₁-C₆ alkyl andoptionally substituted 3 to 8-membered heterocycle.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is substituted C₁-C₆ alkyl. In some embodiments, fora compound or salt of Formula (A), (A*), (I), (IIA), or (IIB), R¹ isselected from substituted C₁-C₆ alkyl, wherein the substituents areselected from hydroxy, oxo, and —O—C₁₋₁₀ alkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is optionally substituted 3 to 8-memberedheterocycle. In some embodiments, for a compound or salt of Formula (A),(A*), (I), (IIA), or (IIB), R¹ is selected from optionally substituted 5to 6-membered heterocycle. In some embodiments, R¹ is monocyclic. Insome embodiments, R¹ is bicyclic. In some embodiments, R¹ is a fusedbicyclic group. In some embodiments, R¹ is a bridged bicyclic group. Insome embodiments, R¹ is optionally substituted 5 membered heterocycle.In some embodiments, R¹ is optionally substituted heteroaryl. In someembodiments, R¹ is optionally substituted heterocycloalkyl. In someembodiments, R¹ contains 0-3 nitrogen and 0-1 oxygen atoms on the ring.

In some embodiments, R¹ contains 1-2 nitrogen and 0-1 oxygen atoms onthe ring. In some embodiments, R¹ contains 1-2 ring nitrogen atoms. Insome embodiments, R¹ contains 2 ring nitrogen atoms. In someembodiments, R¹ contains 1 ring nitrogen atom.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is an optionally substituted 6-membered heterocycle.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is an optionally substituted piperazine. In someembodiments, R¹ is an optionally substituted piperazine, wherein thepiperazine is attached to the rest of the compound (e.g., attached tothe phenyl) via a nitrogen. In some embodiments, for a compound or saltof Formula (A), (A*), (I), (IIA), or (IIB), R¹ is piperazine optionallysubstituted with one or more 1-6 alkyl. In some embodiments, for acompound or salt of Formula (A), (A*), (I), (IIA), or (JIB), R¹ ispiperazine optionally substituted with one or more substituents selectedfrom methyl, ethyl and propyl. In some embodiments, for a compound orsalt of Formula (A), (A*), (I), (IIA), or (JIB), R¹ is piperazineoptionally substituted with one or more methyl. In some embodiments, fora compound or salt of Formula (A), (A*), (I), (IIA), or (IIB), R¹ ispiperazine optionally substituted with one or more 1-6 alkyl, whereinthe alkyl is optionally substituted with hydroxy, halogen, oxo, and—NH₂. In some embodiments, for a compound or salt of Formula (A), (A*),(I), (IIA), or (JIB), R¹ is piperazine optionally substituted with anoxide.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (JIB), the optional substituents on the optionally substitutedpiperazine of R¹ are selected from oxo, —S(O₂)NH₂, and optionallysubstituted C₁₋₁₀ alkyl, wherein the optional substituents on the C₁₋₁₀alkyl are independently selected at each occurrence from one or morehydroxy, halogen, oxo, and —NH₂. In some embodiments, for a compound orsalt of Formula (A), (A*), (I), (IIA), or (IIB), the optionalsubstituents on the optionally substituted piperazine of R¹ are selectedfrom oxo, —S(O₂)NH₂, —S(O₂)N(C₁₋₆ alkyl)₂, —S(O₂)NH(C₁₋₆ alkyl), andoptionally substituted C₁₋₆ alkyl. In some embodiments, for a compoundor salt of Formula (A), (A*), (I), (IIA), or (IIB), R¹ is optionallysubstituted with a heteroalkyl. In some embodiments, R¹ is optionallysubstituted with one or more substituents selected from halogen, —CN,—OH, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂,—NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, and C₃-C₆cycloalkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (JIB), R¹ is an optionally substituted 3 to 10-memberedheterocycle. In some cases, R¹ is an optionally substituted 4- to8-membered heterocycle. In some cases, R¹ is an optionally substituted4-membered heterocycle. In some cases, R¹ is an optionally substituted6-membered heterocycle. In some cases, when R¹ is piperazine, thepiperazine is substituted. In some cases, R¹ is not unsubstitutedpiperazine. In some cases, R¹ is a substituted 3 to 10-memberedheterocycle.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (JIB), for R¹, the optional substituents of the heterocycleare independently selected at each occurrence from one or moresubstituents selected from halogen, —OH, —CN, —NO₂, —NH₂, —N(H)C₁-C₆alkyl, —N(C₁-C₆ alkyl)₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀alkyl, and optionally substituted C₁₋₁₀ alkyl, wherein the optionalsubstituents on the C₁₋₁₀ alkyl are independently selected at eachoccurrence from one or more hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl,—NH₂, —CN, —O—C₁₋₁₀ alkyl, and —NO₂.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (JIB), the optional substituents of R¹ are independentlyselected at each occurrence from one or more substituents selected from—NH₂, —N(H)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, oxo, and optionallysubstituted C₁₋₁₀ alkyl, wherein the optional substituents on the C₁₋₁₀alkyl are independently selected at each occurrence from one or more oxoand —O—C₁₋₁₀ alkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), the optional substituents of R¹ are independentlyselected at each occurrence from one or more substituents selected from—NH₂, —N(H)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, oxo, and optionallysubstituted C₁₋₁₀ alkyl, wherein the optional substituents on the C₁₋₁₀alkyl are independently selected at each occurrence from one or more oxoand —O—C₁₋₁₀ alkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), for R¹, the heterocycle has at least one nitrogen atom,phosphorous atom, or oxygen atom. In some cases, for R¹, the heterocyclehas at least one nitrogen atom. In some cases, for R¹, the heterocyclehas at least two nitrogen atoms. In some cases, for R¹, the heterocyclehas at most two nitrogen atoms. In some cases, for R¹, the heterocyclehas at most one nitrogen atom. In some cases, for R¹, the heterocyclehas two nitrogen atoms. In some cases, for R¹, the heterocycle is aspiro-heterocycle.

In some cases, for R¹, the heterocycle is a bridged heterocycle. In somecases, for R¹, the heterocycle is unsaturated. In some cases, for R¹,the heterocycle is saturated.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

any of which are optionally substituted.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

any of which are optionally substituted with one or more substituentsselected from —NH₂, —N(H)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, oxo, andoptionally substituted C₁₋₁₀ alkyl, wherein the optional substituents onthe C₁₋₁₀ alkyl are independently selected at each occurrence from oneor more oxo and —O—C₁₋₁₀ alkyl. In some embodiments, R¹ is optionallysubstituted with one or more substituents selected from —NH₂, —N(H)C₁-C₆alkyl, —N(C₁-C₆ alkyl)₂, oxo, optionally substituted C₁₋₁₀ heteroalkyl,and optionally substituted C₁₋₁₀ alkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (111B), R¹ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

In some embodiments, some embodiments, for a compound or salt of Formula(A), (A*), (I), (IIA), or (IIB), R¹ is an optionally substituted 6- to10-membered heterocycloalkyl. In some cases, the optional substituentsof the optionally substituted 6- to 10-membered heterocycloalkyl for R¹are selected from C₁₋₆ alkyl. In some cases, the 6- to 10-memberedheterocycloalkyl is a spiro heterocycloalkyl. In some cases, R¹ isselected from optionally substituted piperazine, optionally substituteddiazabicyclo [3.2.1]octane, optionally substituteddiazabicyclo[3.1.1]heptane, optionally substituteddiazaspiro[3.5]nonane, and optionally substituteddiazaspiro[3.3]heptane. In some cases, the optional are selected fromC₁₋₆ alkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is optionally substituted. In some embodiments, R³is optionally substituted with 1 to 4 substituents. In some embodiments,R³ is optionally substituted with 1 to 3 substituents. In someembodiments, R³ is optionally substituted with 1 to 2 substituents. Insome embodiments, R³ is optionally substituted with 1 substituent. Insome embodiments, R³ is optionally substituted with 2 substituents. Insome embodiments, R³ is optionally substituted with 3 substituents.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is selected from optionally substituted C₃₋₆carbocycle. In some embodiments, for a compound or salt of Formula (A),(A*), (I), (IIA), or (IIB), R³ is selected from optionally substitutedC₃₋₆ cycloalkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is optionally substituted phenyl. In someembodiments, for a compound or salt of Formula (A), (A*), (I), (IIA), or(IIB), R³ is a phenyl optionally substituted with one or more halogen.In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is a phenyl optionally substituted with 1-3 halogen.In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is a phenyl optionally substituted with 1-2 halogen.In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is a phenyl optionally substituted with one halogen.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), the optional substituents of phenyl of R³ are selectedfrom halogen and —C₁₋₁₀ haloalkyl. In some embodiments, for a compoundor salt of Formula (A), (A*), (I), (IIA), or (IIB), the optionalsubstituents of phenyl of R³ are selected from halogen and —C₁₋₃haloalkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is unsubstituted. In some embodiments, for acompound or salt of Formula (A), (A*), (I), (IIA), or (IIB), R⁴ issubstituted. In some embodiments, for a compound or salt of Formula (A),(A*), (I), (IIA), or (IIB), R⁴ is substituted with one or moresubstituents selected from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S,—O—C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle. In someembodiments, R⁴ is substituted with one or more substituents selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —O—C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ carbocycle,and 3- to 12-membered heterocycle. In some embodiments, R⁴ issubstituted with one or more substituents selected from halogen, —OH,—CN, —NO₂, —NH₂, oxo, ═S, —O—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, and —O—C₁₋₆alkyl. In some embodiments, R⁴ is substituted with one or moresubstituents selected from halogen, —OH, —NO₂, —NH₂, oxo, —C₁₋₆haloalkyl, and —O—C₁₋₆ alkyl. In some embodiments, R⁴ is substitutedwith one or more halogen. In some embodiments, R⁴ is substituted with 1halogen. In some embodiments, R⁴ is substituted with 2 halogens. In someembodiments, R⁴ is substituted with 3 halogens.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is hydrogen.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is selected from optionally substituted C₁-C₆ alkyland optionally substituted C₃₋₆ carbocycle. In some embodiments, for acompound or salt of Formula (A), (A*), (I), (IIA), or (IIB), R⁴ isoptionally substituted cycloalkyl. In some embodiments, for a compoundor salt of Formula (A), (A*), (I), (IIA), or (IIB), R⁴ is optionallysubstituted aryl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), the optional substituents of C₁-C₆ alkyl of R⁴ areselected from halogen.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), the optional substituents of C₃-C₆ carbocycle of R⁴ areselected from hydroxy. In

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), W is selected from 5- to 6-membered heteroaryl.

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), the 5- to 6-membered heteroaryl of W are selected from imidazole,furan, thiophene, oxazole, isoxazole, thiazole, oxadiazole, thiadiazole,pyridine, pyridazine, pyrimidine, and pyrazine.

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), the 5- to 6-membered heteroaryl of W are selected from imidazole,furan, and pyridine.

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), W is imidazole.

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), W is pyridine.

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), W is selected from optionally substituted 5- to 6-memberedheteroaryl.

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), W is selected from pyridine, imidazole, thiazole, and furan.

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), W is selected from pyridine and imidazole.

In some aspects, the compound or salt of Formula (I) is represented byformula (IIA):

or a pharmaceutically acceptable salt thereof.

In some aspects, the compound or salt of Formula (I) is represented byformula (IIB):

or a pharmaceutically acceptable salt thereof.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is selected from optionally substituted C₁-C₆ alkyland optionally substituted C₆ carbocycle.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is selected from C₁-C₆ alkyl and wherein the C₆carbocycle is substituted with one or more substituents selected fromhalogen and —C₁₋₁₀ haloalkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is C₆ carbocycle substituted with one or moresubstituents selected from halogen.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is phenyl, wherein the phenyl is optionallysubstituted with one or more halogen.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R³ is

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is selected from hydrogen, C₁-C₆ alkyl optionallysubstituted with one or more substituents selected from halogen, andC₅₋₆ carbocycle optionally substituted with one or more substituentsselected from hydroxy and amine.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is unsubstituted C₁-C₆ alkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is substituted C₁-C₆ alkyl, wherein the C₁-C₆ alkylis substituted with one or more halogen.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is selected from C₁-C₆ alkyl optionally substitutedwith one or more substituents selected from fluorine, and C₆ cycloalkylsubstituted with hydroxy.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is selected from

In certain embodiments, R⁴ is

In some embodiments, for a compound or salt of Formula (A, (A*), (I),(IIA), or (IIB), R⁴ is selected from

In some embodiments for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is selected from

In some cases, R⁴ is selected from unsubstituted C₁₋₁₀ alkyl,unsubstituted 3- to 6-membered heterocycle, and optionally substitutedC₃-C₆ carbocycle.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), each R⁴ is selected at each occurrence from C₁₋₁₀alkyl, C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein theC₁₋₁₀ alkyl, C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle are eachoptionally substituted with one or more substituents independentlyselected at each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S,C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is selected from unsubstituted C₁₋₁₀ alkyl,unsubstituted 3- to 6-membered heterocycle, and optionally substitutedC₃-C₆ carbocycle, wherein the optional substituents are independentlyselected from one or more halogen —C₁₋₁₀ haloalkyl.

In some embodiments, f for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), each R⁴ is selected at each occurrence from C₁₋₁₀alkyl, unsubstituted 4-membered heterocycle, and optionally substitutedC₃-C₅ carbocycle, wherein the optional substituents are independentlyselected from one or more halogen —C₁₋₁₀ haloalkyl. In some cases, R⁴ isselected from a C₁₋₁₀ alkyl. In some cases, R⁴ is selected from a4-membered heterocycle. In some cases, R⁴ is a 4-membered heterocycle.In some cases, R⁴ is a saturated 4-membered heterocycle.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R⁴ is selected from

In some cases, R⁴ is selected from

In some cases, R is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from:

—N(R⁵)₂, wherein R⁵ is selected from optionally substituted C₁-C₆ alkyl,wherein the substituents on C₁-C₆ alkyl are independently selected ateach occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo,—C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl,

substituted C₁-C₆ alkyl, wherein the substituents on C₁-C₆ alkyl areindependently selected at each occurrence from one or more halogen, —OH,—NH₂, oxo, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀alkyl);

optionally substituted 6 to 8-membered heterocycle; wherein the optionalsubstituents on the 6 to 8-membered heterocycle are independentlyselected at each occurrence from one or more oxo, —S(O₂)NH₂, —NH₂,—C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, and optionally substituted C₁₋₁₀alkyl, wherein the optional substituents on the C₁₋₁₀ alkyl areindependently selected at each occurrence from one or more hydroxy,halogen, oxo, —C₁₋₁₀ haloalkyl, —NH₂, —CN, and —NO₂.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from:

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from:

substituted C₁-C₆ alkyl, wherein the substituents on C₁-C₆ alkyl areindependently selected at each occurrence from one or more halogen, —OH,oxo, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl;

optionally substituted 6 to 8-membered saturated heterocycle; whereinthe optional substituents are independently selected at each occurrencefrom one or more —S(O₂)NH₂, and optionally substituted C₁₋₁₀ alkyl,wherein the optional substituents on the C₁₋₁₀ alkyl are independentlyselected at each occurrence from one or more hydroxy, halogen, oxo,—C₁₋₁₀ haloalkyl, and —NH₂.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from optionally substituted 6 to8-membered saturated heterocycle; wherein the optional substituents areindependently selected at each occurrence from one or more —S(O₂)NH₂,and optionally substituted C₁₋₁₀ alkyl, wherein the optionalsubstituents on the C₁₋₁₀ alkyl are independently selected at eachoccurrence from one or more hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl, and—NH₂.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from substituted C₁-C₆ alkyl, whereinthe substituents on C₁-C₆ alkyl are independently selected at eachoccurrence from one or more halogen, —OH, oxo, —C₁₋₁₀ haloalkyl, and—O—C₁₋₁₀ alkyl.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from:

substituted C₁-C₆ alkyl, wherein the substituents on C₁-C₆ alkyl areindependently selected at each occurrence from one or more —OH, oxo, and—O—C₁₋₁₀ alkyl;

optionally substituted 6 to 8-membered saturated heterocycle; whereinthe optional substituents are independently selected at each occurrencefrom one or more optionally substituted C₁₋₁₀ alkyl, wherein theoptional substituents on the C₁₋₁₀ alkyl are independently selected ateach occurrence from one or more hydroxy, oxo, —C₁₋₁₀ haloalkyl, and—NH₂.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from:

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is piperazine, wherein the piperazine is optionallysubstituted with one or more substituents independently selected at eachoccurrence from oxo, —S(O₂)NH₂, and C₁₋₁₀ alkyl, wherein the C₁₋₁₀ alkylis optionally substituted with one or more substituents independentlyselected at each occurrence from hydroxy, halogen, oxo, and —NH₂. Insome embodiments, R¹ is piperazine substituted with one or more C₁₋₃alkyl, wherein the C₁₋₃ alkyl is optionally substituted with one or moresubstituents independently selected at each occurrence from hydroxy,halogen, oxo, and —NH₂.

In some embodiments, for a compound or salt of Formula (A), (A*), (I),(IIA), or (IIB), R¹ is selected from

In some embodiments, for a compound or salt of Formula (A), (A*), or(I), the compound is not

In some cases, the compound is not

In some embodiments, for a compound or salt of Formula (A), (A*), or(I),

R¹ is selected from —N(R⁵)₂, wherein R⁵ is selected from optionallysubstituted C₁-C₆ alkyl, wherein the optional substituents on C₁-C₆alkyl are selected from hydroxy;

substituted C₁-C₆ alkyl wherein the substituents are selected fromhydroxy, oxo, and —O—C₁₋₁₀ alkyl; and

optionally substituted 5 to 6-membered heterocycle wherein the optionalsubstituents are selected from oxo, —S(O₂)NH₂, and optionallysubstituted C₁₋₁₀ alkyl, wherein the optional substituents on the C₁₋₁₀alkyl are independently selected at each occurrence from one or morehydroxy, halogen, oxo, and —NH₂;

R³ is optionally substituted phenyl wherein the optional substituents ofphenyl of R³ are selected from halogen and —C₁₋₁₀ haloalkyl;

R⁴ is selected from optionally substituted C₁-C₆ alkyl and optionallysubstituted C₃₋₆ carbocycle wherein the optional substituents of C₁-C₆alkyl of R⁴ are selected from halogen and wherein the optionalsubstituents of C₃-C₆ carbocycle of R⁴ are selected from hydroxy; and

W is selected from imidazole, furan, and pyridine.

In some embodiments, for a compound or salt of Formula (A), (A*), or(I),

R¹ is selected from —N(R⁵)₂, wherein R⁵ is selected from optionallysubstituted C₁-C₆ alkyl, wherein the optional substituents on C₁-C₆alkyl are selected from hydroxy;

substituted C₁-C₆ alkyl wherein the substituents are selected fromhydroxy, oxo, and —O—C₁₋₁₀ alkyl; and

optionally substituted 5 to 6-membered heterocycle wherein the optionalsubstituents are selected from oxo, —S(O₂)NH₂, and optionallysubstituted C₁₋₁₀ alkyl, wherein the optional substituents on the C₁₋₁₀alkyl are independently selected at each occurrence from one or morehydroxy, halogen, oxo, and —NH₂;

R³ is optionally substituted phenyl wherein the optional substituents ofphenyl of R³ are selected from halogen and —C₁₋₁₀ haloalkyl;

R⁴ is selected from optionally substituted C₁-C₆ alkyl and optionallysubstituted C₃₋₆ carbocycle wherein the optional substituents of C₁-C₆alkyl of R⁴ are selected from halogen and wherein the optionalsubstituents of C₃-C₆ carbocycle of R⁴ are selected from hydroxy; and Ware selected from imidazole.

In some embodiments, for a compound or salt of Formula (A), (A*), (IIA),(IIB), or (I), R¹ is selected from

R³ is

and R⁴ is selected from

Included in the present disclosure are salts, particularlypharmaceutically acceptable salts, of the compounds described herein.The compounds of the present invention that possess a sufficientlyacidic, a sufficiently basic, or both functional groups, can react withany of a number of inorganic bases, and inorganic and organic acids, toform a salt. Alternatively, compounds that are inherently charged, suchas those with a quaternary nitrogen, can form a salt with an appropriatecounterion, e.g., a halide such as bromide, chloride, or fluoride,particularly bromide.

Chemical entities having carbon-carbon double bonds or carbon-nitrogendouble bonds may exist in Z- or E-form (or cis- or trans-form).Furthermore, some chemical entities may exist in various tautomericforms. Unless otherwise specified, compounds described herein areintended to include all Z-, E- and tautomeric forms as well.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein, in certain embodiments, exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

The compounds disclosed herein, in some embodiments, are used indifferent enriched isotopic forms, e.g., enriched in the content of ²H,³H, ¹¹C, ¹³C and/or ¹⁴C. In one particular embodiment, the compound isdeuterated in at least one position. Such deuterated forms can be madeby the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Asdescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration canimprove the metabolic stability and or efficacy, thus increasing theduration of action of drugs.

Unless otherwise stated, compounds described herein are intended toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnaturalproportions of atomic isotopes at one or more atoms that constitute suchcompounds. For example, the compounds may be labeled with isotopes, suchas for example, deuterium (2H), tritium (H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C). Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N,¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S,³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, and ¹²⁵I are all contemplated. All isotopicvariations of the compounds of the present invention, whetherradioactive or not, are encompassed within the scope of the presentinvention. In some embodiments, where isotopic variations areillustrated, the remaining atoms of the compound may optionally containunnatural portions of atomic isotopes.

In certain embodiments, the compounds disclosed herein have some or allof the ¹H atoms replaced with ²H atoms. The methods of synthesis fordeuterium-containing compounds are known in the art and include, by wayof non-limiting example only, the following synthetic methods.

Deuterium substituted compounds are synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp;George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compoundsvia Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21;and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32.

Deuterated starting materials are readily available and are subjected tothe synthetic methods described herein to provide for the synthesis ofdeuterium-containing compounds. Large numbers of deuterium-containingreagents and building blocks are available commercially from chemicalvendors, such as Aldrich Chemical Co.

In some embodiments of a compound disclosed herein, one or more of R¹,R³, R⁴, R⁵, W, Z, Y, and R¹⁰ groups comprise deuterium at a percentagehigher than the natural abundance of deuterium.

In some embodiments of a compound disclosed herein, one or morehydrogens are replaced with one or more deuteriums in one or more of thefollowing groups R¹, R³, R⁴, R⁵, W, Z, Y, and R¹⁰.

In some embodiments of a compound disclosed herein, the abundance ofdeuterium in each of R¹, R³, R⁴, R⁵, W, Z, Y, and R¹⁰ is independentlyat least 1%, at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70%, at least 80%, at least 90%, or100% of a total number of hydrogen and deuterium.

In some embodiments of a compound disclosed herein, one or morehydrogens of ring W are replaced with one or more deuteriums.

Compounds of the present invention also include crystalline andamorphous forms of those compounds, pharmaceutically acceptable salts,and active metabolites of these compounds having the same type ofactivity, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof.

The compounds described herein may in some cases exist as diastereomers,enantiomers, or other stereoisomeric forms. Where absolutestereochemistry is not specified, the compounds presented herein includeall diastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Separation of stereoisomers may beperformed by chromatography or by forming diastereomers and separatingby recrystallization, or chromatography, or any combination thereof.(Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racematesand Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporatedby reference for this disclosure). Stereoisomers may also be obtained bystereoselective synthesis.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).The compounds described herein may be in the form of pharmaceuticallyacceptable salts. As well, in some embodiments, active metabolites ofthese compounds having the same type of activity are included in thescope of the present disclosure. In addition, the compounds describedherein can exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the compounds presented herein are alsoconsidered to be disclosed herein.

In certain embodiments, compounds or salts of the compounds may beprodrugs, e.g., wherein a hydroxyl in the parent compound is presentedas an ester or a carbonate, or carboxylic acid present in the parentcompound is presented as an ester. The term “prodrug” is intended toencompass compounds which, under physiologic conditions, are convertedinto pharmaceutical agents of the present disclosure. One method formaking a prodrug is to include one or more selected moieties which arehydrolyzed under physiologic conditions to reveal the desired molecule.In other embodiments, the prodrug is converted by an enzymatic activityof the host animal such as specific target cells in the host animal. Forexample, esters or carbonates (e.g., esters or carbonates of alcohols orcarboxylic acids and esters of phosphonic acids) are preferred prodrugsof the present disclosure.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound as set forth herein areincluded within the scope of the claims. In some cases, some of theherein-described compounds may be a prodrug for another derivative oractive compound.

Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Prodrugsmay help enhance the cell permeability of a compound relative to theparent drug. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. Prodrugs may bedesigned as reversible drug derivatives, for use as modifiers to enhancedrug transport to site-specific tissues or to increase drug residenceinside of a cell.

In some embodiments, the design of a prodrug increases the lipophilicityof the pharmaceutical agent. In some embodiments, the design of aprodrug increases the effective water solubility. See, e.g., Fedorak etal., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovelDelivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporatedherein for such disclosure). According to another embodiment, thepresent disclosure provides methods of producing the above-definedcompounds. The compounds may be synthesized using conventionaltechniques. Advantageously, these compounds are conveniently synthesizedfrom readily available starting materials.

Synthetic chemistry transformations and methodologies useful insynthesizing the compounds described herein are known in the art andinclude, for example, those described in R. Larock, ComprehensiveOrganic Transformations (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

C. Pharmaceutical Compositions

Provided herein, in certain embodiments, are compositions comprising atherapeutically effective amount of any compound or salt of any one ofFormulas (A), (A*), (I), (IIA), or (JIB), (also referred to herein as “apharmaceutical agent”).

Pharmaceutical compositions may be formulated using one or morephysiologically acceptable carriers including excipients and auxiliarieswhich facilitate processing of the pharmaceutical agent intopreparations which are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions is found, for example, in Remington: TheScience and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins, 1999).

The compositions and methods of the present disclosure may be utilizedto treat an individual in need thereof. In certain embodiments, theindividual is a mammal such as a human, or a non-human mammal. Whenadministered to an animal, such as a human, the composition or thepharmaceutical agent, is preferably administered as a pharmaceuticalcomposition comprising, for example, a pharmaceutical agent and apharmaceutically acceptable carrier or excipient. Pharmaceuticallyacceptable carriers are well known in the art and include, for example,aqueous solutions such as water or physiologically buffered saline orother solvents or vehicles such as glycols, glycerol, oils such as oliveoil, or injectable organic esters. In a preferred embodiment, when suchpharmaceutical compositions are for human administration, particularlyfor invasive routes of administration, e.g., routes, such as injectionor implantation, that circumvent transport or diffusion through anepithelial barrier, the aqueous solution is pyrogen-free, orsubstantially pyrogen-free. The excipients can be chosen, for example,to effect delayed release of an agent or to selectively target one ormore cells, tissues or organs. The pharmaceutical composition can be indosage unit form such as tablet, capsule, granule, lyophile forreconstitution, powder, solution, syrup, suppository, injection or thelike. The composition can also be present in a transdermal deliverysystem, e.g., a skin patch. The composition can also be present in asolution suitable for topical administration, such as an eye drop.

The pharmaceutical composition can be used as an inhibitor of tumorimmunosuppression in combination with chemotherapy or an immunecheckpoint inhibitor therapy for cancer. In some case the pharmaceuticalcomposition can be used to treat a fibrotic disease or conditionincluding but not limited to chronic kidney fibrosis (“CKD”), livercirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardialinfarction, skin fibrosis, systemic sclerosis (“SSc”), andgraft-versus-host disease (“GVHD). In some cases, the pharmaceuticalcomposition can be used to treat kidney fibrosis. In some cases, thepharmaceutical composition can be used to treat skin fibrosis. In somecases, the pharmaceutical composition can be used to treat idiopathicpulmonary fibrosis (IPF). In some cases, the pharmaceutical compositioncan be used to treat a disease associated with TNIK kinase.

A pharmaceutically acceptable excipient can contain physiologicallyacceptable agents that act, for example, to stabilize, increasesolubility or to increase the absorption of a compound such as apharmaceutical agent. Such physiologically acceptable agents include,for example, carbohydrates, such as glucose, sucrose or dextrans,antioxidants, such as ascorbic acid or glutathione, chelating agents,low molecular weight proteins or other stabilizers or excipients. Thechoice of a pharmaceutically acceptable excipient, including aphysiologically acceptable agent, depends, for example, on the route ofadministration of the composition. The preparation or pharmaceuticalcomposition can be a self-emulsifying drug delivery system or a selfmicroemulsifying drug delivery system. The pharmaceutical composition(preparation) also can be a liposome or other polymer matrix, which canhave incorporated therein, for example, a compound of the invention.Liposomes, for example, which comprise phospholipids or other lipids,are nontoxic, physiologically acceptable and metabolizable carriers thatare relatively simple to make and administer.

A pharmaceutical composition (preparation) can be administered to asubject by any of a number of routes of administration including, forexample, orally, for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, capsules, including sprinkle capsulesand gelatin capsules, boluses, powders, granules, pastes for applicationto the tongue; absorption through the oral mucosa, e.g., sublingually;anally, rectally or vaginally, for example, as a pessary, cream or foam;parenterally, including intramuscularly, intravenously, subcutaneouslyor intrathecally as, for example, a sterile solution or suspension;nasally; intraperitoneally; subcutaneously; transdermally, for example,as a patch applied to the skin; and topically, for example, as a cream,ointment or spray applied to the skin, or as an eye drop. The compoundmay also be formulated for inhalation. In certain embodiments, acompound may be simply dissolved or suspended in sterile water.

A pharmaceutical composition may be a sterile aqueous or non-aqueoussolution, suspension or emulsion, e.g., a microemulsion. The excipientsdescribed herein are examples and are in no way limiting. An effectiveamount or therapeutically effective amount refers to an amount of theone or more pharmaceutical agents administered to a subject, either as asingle dose or as part of a series of doses, which is effective toproduce a desired therapeutic effect.

Subjects may generally be monitored for therapeutic effectiveness usingassays and methods suitable for the condition being treated, whichassays will be familiar to those having ordinary skill in the art andare described herein. Pharmacokinetics of a pharmaceutical agent, or oneor more metabolites thereof, that is administered to a subject may bemonitored by determining the level of the pharmaceutical agent ormetabolite in a biological fluid, for example, in the blood, bloodfraction, e.g., serum, and/or in the urine, and/or other biologicalsample or biological tissue from the subject. Any method practiced inthe art and described herein to detect the agent may be used to measurethe level of the pharmaceutical agent or metabolite during a treatmentcourse.

The dose of a pharmaceutical agent described herein for treating adisease or disorder may depend upon the subject's condition, that is,stage of the disease, severity of symptoms caused by the disease,general health status, as well as age, gender, and weight, and otherfactors apparent to a person skilled in the medical art. Pharmaceuticalcompositions may be administered in a manner appropriate to the diseaseto be treated as determined by persons skilled in the medical arts. Inaddition to the factors described herein and above related to use ofpharmaceutical agent for treating a disease or disorder, suitableduration and frequency of administration of the pharmaceutical agent mayalso be determined or adjusted by such factors as the condition of thepatient, the type and severity of the patient's disease, the particularform of the active ingredient, and the method of administration. Optimaldoses of an agent may generally be determined using experimental modelsand/or clinical trials. The optimal dose may depend upon the body mass,weight, or blood volume of the subject. The use of the minimum dose thatis sufficient to provide effective therapy is usually preferred. Designand execution of pre-clinical and clinical studies for a pharmaceuticalagent, including when administered for prophylactic benefit, describedherein are well within the skill of a person skilled in the relevantart. When two or more pharmaceutical agents are administered to treat adisease or disorder, the optimal dose of each pharmaceutical agent maybe different, such as less than when either agent is administered aloneas a single agent therapy. In certain particular embodiments, twopharmaceutical agents in combination may act synergistically oradditively, and either agent may be used in a lesser amount than ifadministered alone. An amount of a pharmaceutical agent that may beadministered per day may be, for example, between about 0.01 mg/kg and100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg bodyweight. In other embodiments, the amount of a pharmaceutical agent thatmay be administered per day is between about 0.01 mg/kg and 1000 mg/kg,between about 100-500 mg/kg, or between about 500-1000 mg/kg bodyweight. The optimal dose, per day or per course of treatment, may bedifferent for the disease or disorder to be treated and may also varywith the administrative route and therapeutic regimen.

Pharmaceutical compositions comprising a pharmaceutical agent can beformulated in a manner appropriate for the delivery method by usingtechniques routinely practiced in the art. The composition may be in theform of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid,or gas, e.g., aerosol. In other embodiments, the pharmaceuticalcomposition is administered as a bolus infusion.

Pharmaceutical acceptable excipients are well known in thepharmaceutical art and described, for example, in Rowe et al., Handbookof Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties,and Safety, 5^(th) Ed., 2006, and in Remington: The Science and Practiceof Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).Exemplary pharmaceutically acceptable excipients include sterile salineand phosphate buffered saline at physiological pH. Preservatives,stabilizers, dyes, buffers, and the like may be provided in thepharmaceutical composition. In addition, antioxidants and suspendingagents may also be used. In general, the type of excipient is selectedbased on the mode of administration, as well as the chemical compositionof the active ingredient(s). Alternatively, compositions describedherein may be formulated as a lyophilizate. A composition describedherein may be lyophilized or otherwise formulated as a lyophilizedproduct using one or more appropriate excipient solutions forsolubilizing and/or diluting the pharmaceutical agent(s) of thecomposition upon administration. In other embodiments, thepharmaceutical agent may be encapsulated within liposomes usingtechnology known and practiced in the art. In certain particularembodiments, a pharmaceutical agent is not formulated within liposomesfor application to a stent that is used for treating highly, though nottotally, occluded arteries. Pharmaceutical compositions may beformulated for any appropriate manner of administration described hereinand in the art.

A pharmaceutical composition, e.g., for oral administration or forinjection, infusion, subcutaneous delivery, intramuscular delivery,intraperitoneal delivery or other method, may be in the form of aliquid. A liquid pharmaceutical composition may include, for example,one or more of the following: a sterile diluent such as water, salinesolution, preferably physiological saline, Ringer's solution, isotonicsodium chloride, fixed oils that may serve as the solvent or suspendingmedium, polyethylene glycols, glycerin, propylene glycol or othersolvents; antibacterial agents; antioxidants; chelating agents; buffersand agents for the adjustment of tonicity such as sodium chloride ordextrose. A parenteral composition can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic. Theuse of physiological saline is preferred, and an injectablepharmaceutical composition is preferably sterile. In another embodiment,for treatment of an ophthalmological condition or disease, a liquidpharmaceutical composition may be applied to the eye in the form of eyedrops. A liquid pharmaceutical composition may be delivered orally.

For oral formulations, at least one of the pharmaceutical agentsdescribed herein can be used alone or in combination with appropriateadditives to make tablets, powders, granules or capsules, and ifdesired, with diluents, buffering agents, moistening agents,preservatives, coloring agents, and flavoring agents. The pharmaceuticalagents may be formulated with a buffering agent to provide forprotection of the compound from low pH of the gastric environment and/oran enteric coating. A pharmaceutical agent included in a pharmaceuticalcomposition may be formulated for oral delivery with a flavoring agent,e.g., in a liquid, solid or semi-solid formulation and/or with anenteric coating.

A pharmaceutical composition comprising any one of the pharmaceuticalagents described herein may be formulated for sustained or slow release,also called timed release or controlled release. Such compositions maygenerally be prepared using well known technology and administered by,for example, oral, rectal, intradermal, or subcutaneous implantation, orby implantation at the desired target site. Sustained-releaseformulations may contain the compound dispersed in a carrier matrixand/or contained within a reservoir surrounded by a rate controllingmembrane. Excipients for use within such formulations are biocompatible,and may also be biodegradable; preferably the formulation provides arelatively constant level of active component release. The amount ofpharmaceutical agent contained within a sustained release formulationdepends upon the site of implantation, the rate and expected duration ofrelease, and the nature of the condition, disease or disorder to betreated or prevented.

In certain embodiments, the pharmaceutical compositions comprising apharmaceutical agent are formulated for transdermal, intradermal, ortopical administration. The compositions can be administered using asyringe, bandage, transdermal patch, insert, or syringe-like applicator,as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam,cream, gel, paste. This preferably is in the form of a controlledrelease formulation or sustained release formulation administeredtopically or injected directly into the skin adjacent to or within thearea to be treated, e.g., intradermally or subcutaneously. The activecompositions can also be delivered via iontophoresis.

Preservatives can be used to prevent the growth of fungi and othermicroorganisms. Suitable preservatives include, but are not limited to,benzoic acid, butylparaben, ethyl paraben, methyl paraben,propylparaben, sodium benzoate, sodium propionate, benzalkoniumchloride, benzethonium chloride, benzyl alcohol, cetypyridiniumchloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, andcombinations thereof.

Pharmaceutical compositions comprising a pharmaceutical agent can beformulated as emulsions for topical application. An emulsion containsone liquid distributed in the body of a second liquid. The emulsion maybe an oil-in-water emulsion or a water-in-oil emulsion. Either or bothof the oil phase and the aqueous phase may contain one or moresurfactants, emulsifiers, emulsion stabilizers, buffers, and otherexcipients. The oil phase may contain other oily pharmaceuticallyapproved excipients. Suitable surfactants include, but are not limitedto, anionic surfactants, non-ionic surfactants, cationic surfactants,and amphoteric surfactants. Compositions for topical application mayalso include at least one suitable suspending agent, antioxidant,chelating agent, emollient, or humectant.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents. Liquid sprays may be delivered from pressurized packs,for example, via a specially shaped closure. Oil-in-water emulsions canalso be used in the compositions, patches, bandages and articles. Thesesystems are semisolid emulsions, micro-emulsions, or foam emulsionsystems.

In some embodiments, the pharmaceutical agent described herein can beformulated as in inhalant. Inhaled methods can deliver medicationdirectly to the airway. The pharmaceutical agent can be formulated asaerosols, microspheres, liposomes, or nanoparticles. The pharmaceuticalagent can be formulated with solvents, gases, nitrates, or anycombinations thereof. Compositions described herein are optionallyformulated for delivery as a liquid aerosol or inhalable dry powder.

Liquid aerosol formulations are optionally nebulized predominantly intoparticle sizes that can be delivered to the terminal and respiratorybronchioles. Liquid aerosol and inhalable dry powder formulations arepreferably delivered throughout the endobronchial tree to the terminalbronchioles and eventually to the parenchymal tissue.

Aerosolized formulations described herein are optionally delivered usingan aerosol forming device, such as a jet, vibrating porous plate orultrasonic nebulizer, preferably selected to allow the formation ofaerosol particles having with a mass medium average diameterpredominantly between 1 to 5μ. Further, the formulation preferably hasbalanced osmolarity ionic strength and chloride concentration, and thesmallest aerosolizable volume able to deliver effective dose of thepharmaceutical agent. Additionally, the aerosolized formulationpreferably does not negatively impair the functionality of the airwaysand does not cause undesirable side effects.

Aerosolization devices suitable for administration of aerosolformulations described herein include, for example, jet, vibratingporous plate, ultrasonic nebulizers and energized dry powder inhalers,that are able to nebulize the formulation into aerosol particle sizepredominantly in the size range from 1-5μ. Predominantly in thisapplication means that at least 70% but preferably more than 90% of allgenerated aerosol particles are within 1-5 p range. A jet nebulizerworks by air pressure to break a liquid solution into aerosol droplets.Vibrating porous plate nebulizers work by using a sonic vacuum producedby a rapidly vibrating porous plate to extrude a solvent droplet througha porous plate. An ultrasonic nebulizer works by a piezoelectric crystalthat shears a liquid into small aerosol droplets. A variety of suitabledevices are available, including, for example, AeroNeb™ and AeroDose™vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, Calif.),Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC®and Pari LC Star@ jet nebulizers (Pari Respiratory Equipment, Inc.,Richmond, Va.), and Aerosonic™ (DeVilbiss Medizinische Produkte(Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare,Inc., Vernon Hills, Ill.) ultrasonic nebulizers.

In some embodiments, the pharmaceutical agent(s) can be formulated witholeaginous bases or ointments to form a semisolid composition with adesired shape. In addition to the pharmaceutical agent, these semisolidcompositions can contain dissolved and/or suspended bactericidal agents,preservatives and/or a buffer system. A petrolatum component that may beincluded may be any paraffin ranging in viscosity from mineral oil thatincorporates isobutylene, colloidal silica, or stearate salts toparaffin waxes. Absorption bases can be used with an oleaginous system.Additives may include cholesterol, lanolin (lanolin derivatives,beeswax, fatty alcohols, wool wax alcohols, low HLB(hydrophobellipophobe balance) emulsifiers, and assorted ionic andnonionic surfactants, singularly or in combination.

Controlled or sustained release transdermal or topical formulations canbe achieved by the addition of time-release additives, such as polymericstructures, matrices, that are available in the art. For example, thecompositions may be administered through use of hot-melt extrusionarticles, such as bioadhesive hot-melt extruded film. The formulationcan comprise a cross-linked polycarboxylic acid polymer formulation. Across-linking agent may be present in an amount that provides adequateadhesion to allow the system to remain attached to target epithelial orendothelial cell surfaces for a sufficient time to allow the desiredrelease of the compound.

An insert, transdermal patch, bandage or article can comprise a mixtureor coating of polymers that provide release of the pharmaceutical agentsat a constant rate over a prolonged period of time. In some embodiments,the article, transdermal patch or insert comprises water-soluble poreforming agents, such as polyethylene glycol (PEG) that can be mixed withwater insoluble polymers to increase the durability of the insert and toprolong the release of the active ingredients.

Transdermal devices (inserts, patches, bandages) may also comprise awater insoluble polymer. Rate controlling polymers may be useful foradministration to sites where pH change can be used to effect release.These rate controlling polymers can be applied using a continuouscoating film during the process of spraying and drying with the activecompound. In one embodiment, the coating formulation is used to coatpellets comprising the active ingredients that are compressed to form asolid, biodegradable insert.

A polymer formulation can also be utilized to provide controlled orsustained release. Bioadhesive polymers described in the art may beused. By way of example, a sustained-release gel and the compound may beincorporated in a polymeric matrix, such as a hydrophobic polymermatrix. Examples of a polymeric matrix include a microparticle. Themicroparticles can be microspheres, and the core may be of a differentmaterial than the polymeric shell. Alternatively, the polymer may becast as a thin slab or film, a powder produced by grinding or otherstandard techniques, or a gel such as a hydrogel. The polymer can alsobe in the form of a coating or part of a bandage, stent, catheter,vascular graft, or other device to facilitate delivery of thepharmaceutical agent. The matrices can be formed by solvent evaporation,spray drying, solvent extraction and other methods known to thoseskilled in the art.

Kits with unit doses of one or more of the agents described herein,usually in oral or injectable doses, are provided. Such kits may includea container containing the unit dose, an informational package insertdescribing the use and attendant benefits of the drugs in treatingdisease, and optionally an appliance or device for delivery of thecomposition.

D. Methods of Treatment

The compounds described herein can be used in the preparation ofmedicaments for the prevention or treatment of diseases or conditions.In addition, a method for treating any of the diseases or conditionsdescribed herein in a subject in need of such treatment, involvesadministration of pharmaceutical compositions containing at least onecompound described herein, or a pharmaceutically acceptable salt,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, in therapeutically effective amounts to said subject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determined in amanner recognized in the field according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated,and the subject or host being treated. In general, however, dosesemployed for adult human treatment will typically be in the range ofabout 0.02-about 5000 mg per day, in some embodiments, about 1-about1500 mg per day. The desired dose may conveniently be presented in asingle dose or as divided doses administered simultaneously (or over ashort period of time) or at appropriate intervals, for example as two,three, four or more sub-doses per day. In some embodiments, compoundsand pharmaceutical compositions described herein are administered oncedaily. In some embodiments, compounds and pharmaceutical compositionsdescribed herein are administered twice daily. In some embodiments,compounds and pharmaceutical compositions described herein areadministered 3 times a day. In some embodiments, compounds andpharmaceutical compositions described herein are administered onceweekly. In some embodiments, compounds and pharmaceutical compositionsdescribed herein are administered twice weekly. In some embodiments,compounds and pharmaceutical compositions described herein areadministered 3 to 7 times a week. In some embodiments, compounds andpharmaceutical compositions described herein are administered orally. Insome embodiments, compounds and pharmaceutical compositions describedherein are administered intravenously. In some embodiments, compoundsand pharmaceutical compositions described herein are administeredtopically. For example, a compound described herein can be administeredtopically at doses of 0.001% to 10%.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

In an aspect provided herein, the invention provides for inhibitors ofTNIK kinase. Accordingly, the TNIK kinase inhibitors can be used toinhibit a biological pathway downstream from inhibiting TNIK. In someaspects, the TNIK inhibitor can inhibit fibrillar collagen, and therebycan inhibit biological activity related to regulation of theextracellular matrix, and regulation of remodeling the extracellularmatrix. The TNIK inhibitor can inhibit regulation of cell growth,differentiation, cell migration, proliferation, and metabolism.

In certain embodiments, inhibiting the TNIK can inhibit certain TNIKrelated biological pathways. In certain aspects, the inhibiting of TNIKinhibits the Wnt pathway.

In certain embodiments, the inhibiting of TNIK inhibits cytoskeletalrearrangements. The inhibition of TNIK can inhibit the c-Jun N-terminalkinase pathway. The inhibition of TNIK can inhibit the phosphorylationof Gelsolin. The inhibition of TNIK can inhibit the regulation of thecytoskeleton, such as cytoskeletal rearrangements.

In certain embodiments, the inhibiting of TNIK inhibits carcinogenesis.In certain aspect, the administering of the TNIK inhibitor includes atherapeutically effective amount of the compound sufficient to treatcancer by: inhibiting cancer cell growth; inhibiting cancer cellmigration; inhibiting cancer cell proliferation; or inhibiting cancercell migration.

In certain embodiments, the invention provides a method of treating orpreventing a disease, state or condition in a patient in need thereofcomprising administering to the patient an effective amount of acompound of any one of embodiments of the invention or apharmaceutically acceptable salt thereof. The disease, state orcondition may be selected from the group consisting of colorectalcancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer,prostate cancer, multiple myeloma, chronic myelogenous leukemia, cancermetastasis, fibrosis and psychiatric disorders. In some embodiments, thecancer is colorectal cancer. In some embodiments, the cancer is gastriccancer. In some embodiments, the cancer is breast cancer. In someembodiments, the cancer is lung cancer. In some embodiments, the canceris pancreatic cancer. In some embodiments, the cancer is prostatecancer. In some embodiments, the cancer is multiple myeloma. In someembodiments, the cancer is chronic myelogenous leukemia. In someembodiments, the cancer is cancer metastasis.

In certain embodiments, the cancer is a solid tumor. In certainembodiments, the cancer is not a solid tumor.

In certain embodiments, the inhibiting of TNIK inhibits embryonicdevelopment. As such, the TNIK inhibitor can inhibit pregnancyprogression and thereby be used for terminating a pregnancy.

In some embodiments, the inhibiting of TNIK inhibits TGF beta signaling.The TGF beta signaling pathway is involved in a various processes, andthereby inhibiting the TGF beta signaling pathway can inhibit theseprocesses, some of which are described herein. This can includeinhibiting development of an embryo as described herein for inhibitingprogression of pregnancy. This can include inhibiting cell growth, celldifferentiation, which may be used to inhibit pregnancy progression aswell as inhibiting cancer.

In certain embodiments, inhibiting the TGF beta signaling can be usedfor inhibiting formation of extracellular matrix or over formation ofextracellular matrix and the problems associated therewith (e.g.,fibrosis). In some aspects, the inhibiting of TGF beta signaling byinhibiting TNIK inhibits glycosaminoglycan formation. In some aspects,the inhibiting of TGF beta by inhibiting TNIK inhibits collagenformation. In some aspects, the inhibiting of TNIK inhibits fibrosis. Insome aspects, the inhibited fibrosis is selected from pulmonary fibrosis(e.g., idiopathic or radiation induced), cystic fibrosis, liver fibrosis(e.g., cirrhosis), myocardial fibrosis (e.g., atrial fibrosis,endomyocardial fibrosis, old myocardial infarction), kidney fibrosis,brain fibrosis (e.g., glial scar), arterial fibrosis, arthrofibrosis(e.g., knee, shoulder, other joints), intestinal fibrosis (e.g., Crohn'sdisease), Dupytren's contracture fibrosis (e.g., hands, fingers), keloidfibrosis (e.g., skin), mediastinal fibrosis (e.g., soft tissue of themediastinum), myelofibrosis (e.g., bone marrow), peyronie's diseasefibrosis (e.g., penis), progressive massive fibrosis (e.g., lungs,complication of coal worker's pneumoconiosis), retroperitoneal fibrosis(e.g., soft tissue of the retroperitoneum), scleroderma sclerosisfibrosis (e.g., skin, lungs), adhesive capsulitis fibrosis (e.g.,shoulder), or combinations thereof. In some aspects, the fibrosis isskin fibrosis.

In certain embodiments, the TNIK inhibitor can be used to inhibit theepithelial to mesenchymal transition of cancer cells and/or developmentof fibrosis. In some aspects, this can include inhibiting the Smadsignaling pathways. In some aspects, this can include inhibiting thenon-Smad signaling pathways. In some aspects, this can includeinhibiting Wnt, NF-KB, FAC-Src-paxillin-related focal adhesion, and MAPkinases (e.g., ERK and INK) signaling pathways.

In certain embodiments, the disclosure provides for methods of treatingor preventing a fibrotic disease or condition. In some embodiments, thefibrotic disease or condition is selected from pulmonary fibrosis,cystic fibrosis, liver fibrosis, myocardial fibrosis, kidney fibrosis,brain fibrosis, arterial fibrosis, arthrofibrosis, intestinal fibrosis,Dupytren's contracture fibrosis, keloid fibrosis, mediastinal fibrosis,myelofibrosis, peyronie's disease fibrosis, progressive massivefibrosis, retroperitoneal fibrosis, scleroderma sclerosis fibrosis,adhesive capsulitis fibrosis, or combinations thereof. In someembodiments, the fibrotic disease is selected from liver cirrhosis,pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction,systemic sclerosis (SSc), and graft-versus-host disease (GVHD). In someembodiments, the fibrotic disease is kidney fibrosis.

In certain embodiments, the disclosure provides for methods of treatinga kidney disease. In some embodiments, the kidney disease is chronickidney fibrosis (CKD). In some embodiments, the kidney disease is akidney fibrosis.

In some embodiments, the fibrotic disease is liver cirrhosis. In someembodiments, the fibrotic disease is pulmonary fibrosis. In someembodiments, the fibrotic disease is idiopathic pulmonary fibrosis(IPF).

In some embodiments, the fibrotic disease is kidney fibrosis wherein thedisease is chronic or acute. In some embodiments, the kidney fibrosiscauses glomerulosclerosis or tubulointerstitial fibrosis. In someembodiments, the fibrotic disease is renal interstitial fibrosis. Insome embodiments, the fibrotic disease is acute interstitial nephritis(AIN).

In some embodiments, the fibrotic disease is systemic sclerosis (SSc).In some embodiments, the fibrotic disease is graft-versus-host disease(GVHD). In some embodiments, the fibrotic disease is hypertrophicscarring (HTS).

In some embodiments, provided herein are methods of suppressing fibrosismarkers in a subject such as alpha-smooth muscle actin, or α-SMA, andcollagen by administering compounds and pharmaceutical compositions ofthe present disclosure.

In some embodiments, provided herein are methods of antagonizingfibroblast-to-myofibroblast transition (FMT) in primary human lungfibroblasts. In some embodiments, provided herein are methods ofantagonizing epithelial-mesenchymal transition (EMT) in primary humanepithelial cells.

In some embodiments, provided herein are methods of reducing collagenand hydroxyproline in the skin by administering compounds andpharmaceutical compositions of the present disclosure, e.g., via oral ortopical administration.

In some embodiments, compounds and pharmaceutical compositions describedherein are administered with a second therapeutic agent. In someembodiments, the second therapeutic agent is Pirfenidone. In someembodiments, compounds and pharmaceutical compositions described hereinare administered with sub-therapeutic doses of Pirfenidone.

Compounds and pharmaceutical compositions described herein can beadministered to a subject for a period of about 1 day to about 30 yearsor more. In some embodiments, compounds and pharmaceutical compositionsdescribed herein are administered to a subject for a period of over ayear. In some embodiments, compounds and pharmaceutical compositionsdescribed herein are administered to a subject for a period of 3 monthsto 5 years. In some embodiments, compounds and pharmaceuticalcompositions described herein are administered to a subject for a periodof 1 month to 1 year or any numbers or ranges therebetween (e.g., 2-3months, 1-6 months, 6-12 months, 1-3 months, etc.).

E. Further Embodiments

In an aspect, provided herein is a compound represented by Formula(IIA):

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is piperazine, wherein the piperazine is optionally substituted    with one or more substituents independently selected at each    occurrence from oxo, —S(O₂)NH₂, and C₁₋₁₀ alkyl, wherein the C₁₋₁₀    alkyl is optionally substituted with one or more substituents    independently selected at each occurrence from hydroxy, halogen,    oxo, and —NH₂;-   R³ is phenyl, wherein the phenyl is optionally substituted with one    or more halogen; and-   R⁴ is unsubstituted C₁-C₆ alkyl.

In some embodiments, R⁴ is selected from

In some embodiments, R³ is selected from

In some embodiments, R¹ is piperazine substituted with one or more C₁₋₃alkyl, wherein the C₁₋₃ alkyl is optionally substituted with one or moresubstituents independently selected at each occurrence from hydroxy,halogen, oxo, and —NH₂.

In some embodiments, R¹ is selected from

In some embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In another aspect, provide herein is a method of treating a fibroticdisease or condition, comprising administering a compound describedherein, or a pharmaceutically acceptable salt thereof, to a subject inneed thereof.

In some embodiments, the fibrotic disease or condition is idiopathicpulmonary fibrosis (IPF).

In some embodiments, the fibrotic disease or condition is skin fibrosis.

In another aspect, provided herein is a pharmaceutical compositioncomprising (i) a compound represented by Formula (IIA):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is piperazine, wherein the piperazine is optionally        substituted with one or more substituents independently selected        at each occurrence from oxo, —S(O₂)NH₂, and C₁₋₁₀ alkyl, wherein        the C₁₋₁₀ alkyl is optionally substituted with one or more        substituents independently selected at each occurrence from        hydroxy, halogen, oxo, and —NH₂;    -   R³ is phenyl, wherein the phenyl is optionally substituted with        one or more halogen; and    -   R⁴ is unsubstituted C₁-C₆ alkyl; and        (ii) a pharmaceutically acceptable excipient.

In some embodiments, R³ is selected from

R³ is selected from

and

R⁴ is selected from

In some embodiments, the compound represented by Formula (IIA) is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound represented by Formula (IIA) is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound represented by Formula (IIA) is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound represented by Formula (IIA) is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound represented by Formula (IIA) is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound represented by Formula (IIA) is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound represented by Formula (IIA) is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound represented by Formula (IIA) is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound represented by Formula (IIA) is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound represented by Formula (IIA) is

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a compound represented by Formula(I),

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from:    -   —N(R⁵)₂, wherein each R⁵ is independently selected from        hydrogen, and optionally substituted C₁-C₆ alkyl, wherein the        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected at each occurrence from        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀ haloalkyl,        —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle,        and 3- to 12-membered heterocycle;    -   substituted C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally        substituted with one or more substituents independently selected        at each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S,        —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀        alkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3-        to 12-membered heterocycle; and    -   optionally substituted 3 to 8-membered heterocycle; wherein the        3 to 8-membered heterocycle is optionally substituted with one        or more substituents independently selected at each occurrence        from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle, and optionally        substituted C₁₋₁₀ alkyl, wherein the C₁₋₁₀ alkyl is optionally        substituted with one or more substituents independently selected        at each occurrence from hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl,        —NH₂, —CN, and —NO₂;-   R³ is selected from optionally substituted C₁-C₆ alkyl, optionally    substituted 3- to 10-membered heterocycle and optionally substituted    C₃₋₁₀ carbocycle, wherein each of the alkyl, heterocycle and    carbocycle is optionally substituted with one or more substituents    independently selected at each occurrence from halogen, —OH, —CN,    —NO₂, —NH₂, oxo, ═S, C₁₋₆ alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl,    C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3- to    12-membered heterocycle;-   R⁴ is selected from:    -   hydrogen;    -   optionally substituted C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is        optionally substituted with one or more substituents        independently selected at each occurrence from halogen, —OH,        —CN, —NO₂, —NH₂, oxo, ═S, —O—C₁₋₁₀ alkyl, —C₁₋₁₀ haloalkyl,        —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle,        and 3- to 12-membered heterocycle; and    -   optionally substituted C₃₋₁₀ carbocycle, wherein the C₃₋₁₀        carbocycle is optionally substituted with one or more        substituents independently selected at each occurrence from        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀ alkyl, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle;-   W is selected from optionally substituted 5- to 8-membered    heteroaryl, wherein the 5- to 8-membered heteroaryl is optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S,    —S(O₂)NH₂, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀    alkynyl, C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; and    -   wherein when R¹ is methylpiperazine and W is pyridine, then R⁴        is not methyl; and when W is furan and R⁴ is cyclopentyl or        cyclohexyl, then R¹ is not ethan-1-one.

In some embodiments, R¹ is selected from —N(R⁵)₂, wherein each R⁵ isindependently selected from optionally substituted C₁-C₆ alkyl, whereinthe optional substituents on C₁-C₆ alkyl are selected from hydroxy, R¹is selected from substituted C₁-C₆ alkyl and optionally substituted 3 to8-membered heterocycle.

In some embodiments, R¹ is selected from substituted C₁-C₆ alkyl,wherein the optional substituents are selected from hydroxy, oxo, and—O—C₁₋₁₀ alkyl.

In some embodiments, R¹ is selected from optionally substituted 5 to6-membered heterocycle.

In some embodiments, R¹ is an optionally substituted 6-memberedheterocycle.

In some embodiments, R¹ is an optionally substituted piperazine.

In some embodiments, the optional substituents on the piperazine areselected from oxo, —S(O₂)NH₂, and optionally substituted C₁₋₁₀ alkyl,wherein the optional substituents on the C₁₋₁₀ alkyl are independentlyselected at each occurrence from one or more hydroxy, halogen, oxo, and—NH₂.

In some embodiments, R³ is selected from optionally substituted C₃₋₆carbocycle.

In some embodiments, R³ is optionally substituted phenyl.

In some embodiments, the optional substituents of the phenyl areselected from halogen and —C₁₋₁₀ haloalkyl.

In some embodiments, R⁴ is selected from optionally substituted C₁-C₆alkyl and optionally substituted C₃₋₆ carbocycle.

In some embodiments, R⁴ is C₁-C₆ alkyl and is optionally substitutedwith one or more halogen.

In some embodiments, R⁴ is C₃₋₆ carbocycle and is optionally substitutedwith one or more hydroxy.

In some embodiments, W is selected from 5- to 6-membered heteroaryl.

In some embodiments, the 5- to 6-membered heteroaryl of W are selectedfrom imidazole, thiophene, oxazole, isoxazole, thiazole, oxadiazole,thiadiazole, pyridazine, pyrimidine, pyrazine, and triazine.

In some embodiments, the 5- to 6-membered heteroaryl of W are selectedfrom imidazole, furan, and pyridine.

In some embodiments, W is imidazole.

In some embodiments, W is selected from optionally substituted 5- to6-membered heteroaryl.

In some embodiments, W is selected from optionally substituted pyridine,imidazole, thiazole, and furan.

In some embodiments, W is selected from optionally substituted pyridineand imidazole.

In some embodiments, the compound is represented by formula (IIA):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is represented by formula (IIB).

or a pharmaceutically acceptable salt thereof.

In some embodiments, R³ is selected from optionally substituted C₁-C₆alkyl and optionally substituted C₆ carbocycle.

In some embodiments, R³ is selected from C₁-C₆ alkyl and substituted C₆carbocycle, and wherein the C₆ carbocycle is substituted with one ormore substituents selected from halogen and —C₁₋₁₀ haloalkyl.

In some embodiments, R³ is selected from

In some embodiments, R³ is C₆ carbocycle substituted with one or moresubstituents selected from halogen.

In some embodiments, R³ is selected from

In some embodiments, R³ is

In some embodiments, R⁴ is selected from hydrogen, C₁-C₆ alkyloptionally substituted with one or more substituents selected fromhalogen, and C₅₋₆ carbocycle optionally substituted with one or moresubstituents selected from hydroxy and amine.

In some embodiments, R⁴ is selected from

In some embodiments, R⁴ is selected from C₁-C₆ alkyl optionallysubstituted with one or more substituents selected from fluorine, and C₆cycloalkyl substituted with hydroxy.

In some embodiments, R⁴ is selected from

In some embodiments, R⁴ is selected from

In some embodiments, R⁴ is

In some embodiments, R¹ is selected from:

—N(R⁵)₂, wherein R⁵ is selected from optionally substituted C₁-C₆ alkyl,wherein the substituents on C₁-C₆ alkyl are independently selected ateach occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo,—C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl,

substituted C₁-C₆ alkyl, wherein the substituents on C₁-C₆ alkyl areindependently selected at each occurrence from one or more halogen, —OH,—NH₂, oxo, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀alkyl);

optionally substituted 6 to 8-membered heterocycle; wherein the optionalsubstituents on the 6 to 8-membered heterocycle are independentlyselected at each occurrence from one or more oxo, —S(O₂)NH₂, —NH₂,—C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, and optionally substituted C₁₋₁₀alkyl, wherein the optional substituents on the C₁₋₁₀ alkyl areindependently selected at each occurrence from one or more hydroxy,halogen, oxo, —C₁₋₁₀ haloalkyl, —NH₂, —CN and —NO₂.

In some embodiments, R¹ is selected from

In some embodiments, R¹ is selected from

In some embodiments, R¹ is selected from

In some embodiments, R¹ is selected from:

substituted C₁-C₆ alkyl, wherein the substituents on C₁-C₆ alkyl areindependently selected at each occurrence from one or more halogen, —OH,oxo, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl;

optionally substituted 6 to 8-membered saturated heterocycle; whereinthe optional substituents are independently selected at each occurrencefrom one or more —S(O₂)NH₂, and optionally substituted C₁₋₁₀ alkyl,wherein the optional substituents on the C₁₋₁₀ alkyl are independentlyselected at each occurrence from one or more hydroxy, halogen, oxo,—C₁₋₁₀ haloalkyl, and —NH₂.

In some embodiments, R¹ is selected from

In some embodiments, R¹ is selected from optionally substituted 6 to8-membered saturated heterocycle; wherein the optional substituents areindependently selected at each occurrence from one or more —S(O₂)NH₂,and optionally substituted C₁₋₁₀ alkyl, wherein the optionalsubstituents on the C₁₋₁₀ alkyl are independently selected at eachoccurrence from one or more hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl, and—NH₂.

In some embodiments, R¹ is selected from

In some embodiments, R¹ is selected from substituted C₁-C₆ alkyl,wherein the substituents on C₁-C₆ alkyl are independently selected ateach occurrence from one or more halogen, —OH, oxo, —C₁₋₁₀ haloalkyl,and —O—C₁₋₁₀ alkyl.

In some embodiments, R¹ is selected from

In some embodiments, R¹ is selected from:

substituted C₁-C₆ alkyl, wherein the substituents on C₁-C₆ alkyl areindependently selected at each occurrence from one or more —OH, oxo, and—O—C₁₋₁₀ alkyl;

optionally substituted 6 to 8-membered saturated heterocycle; whereinthe optional substituents are independently selected at each occurrencefrom one or more optionally substituted C₁₋₁₀ alkyl, wherein theoptional substituents on the C₁₋₁₀ alkyl are independently selected ateach occurrence from one or more hydroxy, oxo, —C₁₋₁₀ haloalkyl, and—NH₂.

In some embodiments, R¹ is selected from:

In some embodiments, the compound is

or a pharmaceutically acceptable salt of any one thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt of any one thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt of any one thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt of any one thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt of any one thereof.

In another aspect, provided herein is a pharmaceutical compositioncomprising a compound of Formula (I) or salt thereof, and apharmaceutically acceptable excipient.

In another aspect, provided herein is a method of treating or preventinga disease, comprising administering a compound of Formula (I), or saltthereof, to a subject in need thereof.

In some embodiments, the disease is cancer.

In some embodiments, the cancer is selected from colorectal cancer,gastric cancer, breast cancer, lung cancer, pancreatic cancer, prostatecancer, multiple myeloma, chronic myelogenous leukemia, cancermetastasis, fibrosis, and psychiatric disorder.

In some embodiments, the disease is a fibrotic disease or conditionselected from liver cirrhosis, pulmonary fibrosis, renal interstitialfibrosis, myocardial infarction, systemic sclerosis (SSc), andgraft-versus-host disease (GVHD).

In some embodiments, the disease is kidney fibrosis.

In some embodiments, the disease is skin fibrosis.

In some embodiments, the disease is idiopathic pulmonary fibrosis (IPF).

In some embodiments, the disease is associated with TNIK kinase.

In another aspect, provided herein is a method of treating or preventinga disease comprising inhibiting TNIK kinase by administering a compoundof Formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of treating or preventingdisease comprising inhibiting MAP4K4 kinase by administering a compoundof Formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a compound represented by Formula(A):

or a pharmaceutically acceptable salt thereof, wherein:

-   Z is selected from optionally substituted 3- to 12-membered    heterocycle and optionally substituted C₃-C₁₂ carbocycle, wherein    the substituents on each are independently selected at each    occurrence from one or more —N(R¹⁰)₂, halogen, —OH, —CN, —NO₂, —NH₂,    oxo, ═S, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀    alkynyl, C₁-C₁₀ alkyl, C₃₋₁₂ carbocycle, and 3- to 12-membered    heterocycle;    -   wherein the C₁-C₁₀ alkyl is optionally substituted with one or        more substituents independently selected at each occurrence from        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀ haloalkyl,        —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl), C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3- to 12-membered        heterocycle;    -   wherein the C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        are each optionally substituted at each occurrence from one or        more substituents independently selected from halogen, —OH, —CN,        —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀        alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle, and optionally substituted C₁₋₁₀ alkyl,        wherein the optional substituents on the C₁₋₁₀ alkyl are        independently selected at each occurrence from one or more        hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl, —NH₂, —CN, and —NO₂;-   R¹⁰ is selected from optionally substituted C₁-C₆ alkyl, wherein the    optional substituents on C₁-C₆ alkyl are independently selected at    each occurrence from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo,    ═S, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,    C₃₋₁₂ carbocycle, 3- to 12-membered heterocycle;-   W is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl; and-   Y is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.

In another aspect, provided herein is a compound represented by Formula(A*):

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from:    -   —N(R⁵)₂, wherein R⁵ is selected from hydrogen, and optionally        substituted C₁-C₆ alkyl, wherein the optional substituents on        C₁-C₆ alkyl are independently selected at each occurrence from        one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle;    -   substituted C₁-C₆ alkyl, wherein the substituents on C₁-C₆ alkyl        are independently selected at each occurrence from one or more        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀ haloalkyl,        —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl), C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, 3- to 12-membered        heterocycle;    -   optionally substituted 3 to 8-membered heterocycle; wherein the        optional substituents on the 3 to 8-membered heterocycle are        independently selected at each occurrence from one or more        halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀        haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle, and optionally        substituted C₁₋₁₀ alkyl, wherein the optional substituents on        the C₁₋₁₀ alkyl are independently selected at each occurrence        from one or more hydroxy, halogen, oxo, —C₁₋₁₀ haloalkyl, —NH₂,        —CN, and —NO₂;-   W is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl; and-   Y is selected from optionally substituted 5- to 8-membered    heterocycle and optionally substituted C₃-C₈ carbocycle, wherein the    substituents on each are independently selected at each occurrence    from one or more halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —C₁₋₁₀    haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂    carbocycle, 3- to 12-membered heterocycle, wherein the C₃₋₁₂    carbocycle and 3- to 12-membered heterocycle are each optionally    substituted with one or more substituents independently selected at    each occurrence from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₁₀    alkyl, —C₁₋₁₀ haloalkyl, and —O—C₁₋₁₀ alkyl.

In another aspect, provided herein is a pharmaceutical compositioncomprising a compound of Formula (A) or (A*), or a salt thereof, and apharmaceutically acceptable excipient.

In another aspect, provided herein is a method of treating or preventinga disease, comprising administering a compound of Formula (A) or (A*),or a salt thereof, to a subject in need thereof.

In some embodiments, the disease is cancer.

In some embodiments, the cancer is selected from colorectal cancer,gastric cancer, breast cancer, lung cancer, pancreatic cancer, prostatecancer, multiple myeloma, chronic myelogenous leukemia, cancermetastasis, fibrosis, and psychiatric disorders.

In some embodiments, the disease is a fibrotic disease or conditionselected from pulmonary fibrosis, cystic fibrosis, liver fibrosis,myocardial fibrosis, kidney fibrosis, brain fibrosis, arterial fibrosis,arthrofibrosis, intestinal fibrosis, Dupytren's contracture fibrosis,keloid fibrosis, mediastinal fibrosis, myelofibrosis, peyronie's diseasefibrosis, progressive massive fibrosis, retroperitoneal fibrosis,scleroderma sclerosis fibrosis, and adhesive capsulitis fibrosis.

In some embodiments, the disease is a fibrotic disease or conditionselected from liver cirrhosis, pulmonary fibrosis, renal interstitialfibrosis, myocardial infarction, systemic sclerosis (SSc), andgraft-versus-host disease (GVHD).

In some embodiments, the disease is kidney fibrosis.

In some embodiments, the disease is skin fibrosis.

In some embodiments, the disease is idiopathic pulmonary fibrosis (IPF).

In some embodiments, the disease is associated with TNIK kinase.

In another aspect, provided herein is a method of treating or preventinga disease comprising inhibiting TNIK kinase by administering a compoundof Formula (A) or (A*), or a salt thereof to a subject in need thereof.

In another aspect, provided herein is a method of treating or preventingdisease comprising inhibiting MAP4K4 kinase by administering a compoundof Formula (A) or (A*), or salt thereof to a subject in need thereof.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention. The following examples further illustrate theinvention but, of course, should not be construed as in any way limitingits scope.

The following synthetic schemes are provided for purposes ofillustration, not limitation. The following examples illustrate thevarious methods of making compounds described herein. It is understoodthat one skilled in the art may be able to make these compounds bysimilar methods or by combining other methods known to one skilled inthe art. It is also understood that one skilled in the art would be ableto make, in a similar manner as described below by using the appropriatestarting materials and modifying the synthetic route as needed. Ingeneral, starting materials and reagents can be obtained from commercialvendors or synthesized according to sources known to those skilled inthe art or prepared as described herein.

Illustrative Synthesis Schemes

The compounds and salts of Formulas (A), (A*), (I), (IIA), or (IIB) canbe synthesized according to one or more illustrative schemes hereinand/or techniques known in the art. Materials used herein are eithercommercially available or prepared by synthetic methods generally knownin the art. These schemes are not limited to the compounds listed in theexamples or by any particular substituents, which are employed forillustrative purposes. Although various steps are described and depictedin the synthesis schemes below, the steps in some cases may be performedin a different order than the order shown below. Numberings or R groupsin each scheme do not necessarily correspond to that of the claims orother schemes or tables herein.

In some embodiments, compounds of Table 1 may be prepared according tothe synthesis schemes below.

Example 1: Synthesis of Compound 102

Example 2: General procedure for preparation of4-(4-fluorophenyl)-5-iodo-1-isopropyl-1H-imidazole (Compound B)

To a solution of Compound A (35 g, 171.36 mmol, 1 eq) and NIS (115.66 g,514.09 mmol, 3 eq) in DCM (210 mL) was added TFA (5.86 g, 51.41 mmol,3.81 mL, 0.3 eq) at 20° C. The mixture was stirred at 20° C. for 16 h.TLC (PE:EA=1:1) showed reactant 1 (Rf=0.4) was consumed and a new spot(Rf=0.6) was detected. The mixture was poured to aq NaNO₂ (1000 mL). Themixture was extracted with EA (500 mL×3). The combined organic layerswere washed with brine (500 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, PE:EA=5:1-1:1) to afforddesired compound. Compound B (14 g, 37.74 mmol, 22.02% yield, 89%purity) was obtained as yellow solid, which was determined by ¹HNMR andLCMS. LCMS: Retention time: 0.743 min, (M+H)=331.1. ¹HNMR: (400 MHz,DMSO-d₆), δ=8.15 (s, 1H), 7.92-7.85 (m, 2H), 7.29-7.19 (m, 2H),4.50-4.31 (m, 1H), 1.47 (d, J=6.8 Hz, 6H).

Example 3: General procedure for preparation of4-(4-fluorophenyl)-1-isopropyl-5-(tributylstannyl)-1H-imidazole(Compound C)

To a solution of Compound B (2 g, 6.06 mmol, 1 eq) in THE (20 mL) wasadded n-BuLi (2.5 M, 3.15 mL, 1.3 eq) and tributyl(chloro)stannane (2.96g, 9.09 mmol, 2.44 mL, 1.5 eq) slowed at −70° C. The mixture was stirredat −70° C. for 0.5 h. LCMS showed reactant 1 was consumed and 74% ofdesired mass was detected. The mixture was poured to aq NH₄Cl (100 mL)and aq KF (100 mL). The mixture was extracted with EA (100 mL*3). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,PE:EA=50:1-3:1) to afford desired compound. Compound C (2 g, 4.05 mmol,66.93% yield) was obtained as colorless oil, which was determined by¹HNMR. LCMS: Retention time: 0.982 min, (M+H)=492.9. ¹H NMR: (400 MHz,DMSO-d₆), δ=8.05 (s, 1H), 7.46-7.31 (m, 2H), 7.27-7.07 (m, 2H), 4.18 (s,1H), 1.48 (d, J=6.8 Hz, 6H), 1.39-1.30 (m, 5H), 1.29-1.10 (m, 8H),0.97-0.90 (m, 5H), 0.80 (t, J=7.4 Hz, 9H).

Example 4: General procedure for preparation of ethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate(Compound I)

To a solution of NaH (8.56 g, 214.07 mmol, 60% purity, 1.5 eq) in THE(200 mL) was added a mixture of Compound H (20 g, 142.71 mmol, 1 eq) inTHE (100 mL) at 0° C. The mixture was stirred at 0° C. for 20 min, andthen stirred at 20° C. for 30 min. SEM-C₁ (35.69 g, 214.07 mmol, 37.89mL, 1.5 eq) was added to the mixture at 0° C. The mixture was stirred at20° C. for 16 hrs. TLC (PE:EA=1:1) showed reactant 1 (Rf=0.1) consumedand a new spot (Rf=0.2) was observed. The mixture was poured into sat.NH₄Cl (200 mL), and then extracted with EA (100 mL×2). The combinedorganic layers were washed with brine (20 mL×2), dried over Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatography (PE:EA=5:1-1:1). Compound I (15.9g, 58.80 mmol, 41.20% yield) was obtained as yellow oil, which wasdetermined by HNMR. 1H NMR: (400 MHz, CHLOROFORM-d), δ=7.72 (d, J=1.4Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 5.30 (s, 2H), 4.37 (q, J=7.2 Hz, 2H),3.49 (dd, J=7.8, 8.7 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 0.98-0.85 (m, 2H),0.04-−0.06 (m, 10H).

Example 5: General procedure for preparation of ethyl2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate(Compound J)

To a solution of Compound I (14.5 g, 53.62 mmol, 1 eq) in CHCl₃ (150 mL)was added NBS (9.54 g, 53.62 mmol, 1 eq) and AIBN (880.56 mg, 5.36 mmol,0.1 eq) at 20° C. The mixture was stirred at 60° C. for 5 hrs. TLC(PE:EA=1:1) showed reactant 1 (Rf=0.2) consumed and a new spot (Rf=0.5)was observed. The mixture was concentrated in vacuo to give a residue.The residue was purified by silica gel chromatography (PE:EA=5:1-1:1).Compound J (11 g, 31.49 mmol, 58.73% yield) was obtained as yellowsolid, which was determined by HNMR. ¹H NMR: (400 MHz, CHLOROFORM-d),δ=7.76 (s, 1H), 5.31 (s, 2H), 4.38 (q, J=7.2 Hz, 2H), 3.61-3.49 (m, 2H),1.38 (t, J=7.2 Hz, 3H), 1.01-0.85 (m, 2H), 0.05-−0.07 (m, 9H).

Example 6: General procedure for preparation of ethyl5′-(4-fluorophenyl)-3′-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3′H-[2,4′-biimidazole]-4-carboxylate(Compound D)

To a solution of Compound C (300 mg, 608.17 μmol, 1 eq) and Compound J(318.64 mg, 912.25 μmol, 1.5 eq) in toluene (2 mL) was added[2-(2-aminophenyl)phenyl]-chloro-palladium;bis(1-adamantyl)-butyl-phosphane (120.00 mg, 179.47 μmol, 2.95 e-1 eq)under N2 at 20° C. The mixture was stirred at 110° C. for 16 h. LCMSshowed reactant 1 was consumed and 58% of desired mass was detected. Themixture was concentrated in vacuo to afford residue. The residue waspurified by prep-HPLC (column: Phenomenex luna C18 150*40 mm*15 um;mobile phase: [water(0.225% FA)−ACN]; B %: 54%-64%,14 min) to afforddesired compound. Compound D (60 mg, 125.68 μmol, 20.67% yield, 99%purity) was obtained as brown oil, which was determined by ¹HNMR andLCMS. Compound D (100 mg, 84.63 μmol, 13.92% yield, 40% purity) wasobtained as brown oil, which was determined by LCMS. LCMS: Retentiontime: 0.920 min, (M+H)=473.1. LCMS: Retention time: 0.823 min,(M+H)=473.3. LCMS: Retention time: 0.842 min, (M+H)=473.3. ¹H NMR: (400MHz, DMSO-d₆), δ=8.41 (s, 1H), 8.24 (s, 1H), 7.42-7.34 (m, 2H),7.27-7.19 (m, 2H), 5.17-4.92 (m, 2H), 4.51-4.34 (m, 2H), 4.24-4.07 (m,1H), 3.37-3.30 (m, 2H), 1.54-1.41 (m, 9H), 0.67 (br d, J=2.6 Hz, 2H),0.02-−0.02 (m, 9H).

Example 7: General procedure for preparation of5′-(4-fluorophenyl)-3′-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3′H-[2,4′-biimidazole]-4-carboxylicacid (Compound E)

To a solution of Compound D (50.00 mg, 105.79 μmol, 1 eq) in THE (1 mL)and H₂O (1 mL) was added LiOH.H₂O (8.88 mg, 211.58 μmol, 2 eq) at 20° C.The mixture was stirred at 20° C. for 4 h. LCMS showed reactant 1 wasconsumed and 93% of desired mass was detected. To the mixture was added1N HCl (10 mL). The mixture was extracted with EA (20 mL*3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give crudeproduct. Compound E (50 mg, crude) was obtained as colorless oil. LCMS:Retention time: 0.778 min, (M+H)=445.3.

Example 8: General procedure for preparation of methyl3-(4-(5′-(4-fluorophenyl)-3′-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamido)phenyl)propanoate(Compound F)

To a solution of Compound E (50 mg, 112.47 μmol, 1 eq) and Compound GG(30.23 mg, 168.70 μmol, 1.5 eq) in DMF (2 mL) was added HATU (64.15 mg,168.70 μmol, 1.5 eq) and DIPEA (43.61 mg, 337.40 μmol, 58.77 μL, 3 eq)at 20° C. The mixture was stirred at 20° C. for 2 h.

LCMS showed reactant 1 was consumed and 82% of desired mass wasdetected. The mixture was poured to H₂O (20 mL). The mixture wasextracted with EA (20 mL*3). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give crude product. Compound F (65 mg, crude) wasobtained as colorless oil. LCMS: Retention time: 0.978 min, (M+H)=606.1.

Example 9: General procedure for preparation of methyl3-(4-(5′-(4-fluorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamido)phenyl)propanoate(Compound G)

To a solution of Compound F (60 mg, 99.05 μmol, 1 eq) in DCM (2 mL) wasadded TFA (1.54 g, 13.51 mmol, 1 mL, 136.36 eq) at 20° C. The mixturewas stirred at 20° C. for 8 h. LCMS showed reactant 1 was consumed and80% of desired mass was detected. The mixture was poured to aq NaHCO₃(20mL). The mixture was extracted with EA (20 mL*3). The combined organiclayers were washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give crude product. Compound G(50 mg, crude) was obtained as colorless oil. LCMS: Retention time:0.748 min, (M+H)=476.3.

Example 10: General procedure for preparation of3-(4-(5′-(4-fluorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamido)phenyl)propanoicacid (Compound 102)

To a solution of Compound G (40 mg, 84.12 μmol, 1 eq) in THE (1 mL) andH₂O (1 mL) was added LiOH.H₂O (35.30 mg, 841.20 μmol, 10 eq) at 20° C.The mixture was stirred at 20° C. for 2 h. LCMS showed reactant 1 wasconsumed and 74% of desired mass was detected. The mixture was poured to1N HCl (100 mL). The mixture was extracted with EA (20 mL*3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18Ultra 150*50 mm*3 μm; mobile phase: [water(0.225% FA)−ACN]; B %:18%-38%,10 min) to afford desired compound. Compound 102 (14.8 mg, 31.59μmol, 37.55% yield, 98.5% purity) was obtained as yellow solid, whichwas determined by ¹HNMR, LCMS and HPLC and F NMR. LCMS: Retention time:0.692 min, (M+H)=462.3. LCMS: Retention time: 0.673 min, (M+H)=462.3.HPLC: Retention time: 1.434 min. ¹HNMR: (400 MHz, DMSO-d₆),δ=13.30-12.87 (m, 1H), 9.86 (br s, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.72(br d, J=7.8 Hz, 2H), 7.43-7.35 (m, 2H), 7.25-7.07 (m, 5H), 4.30-4.18(m, 1H), 2.79 (t, J=7.6 Hz, 2H), 2.53 (br s, 2H), 1.40 (d, J=6.8 Hz,6H).

Example 11: Synthesis of Compound 112

Example 12: General procedure for preparation of5′-(4-fluorophenyl)-3′-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound K)

To a mixture of Compound E (6.5 g, 14.62 mmol, 1 eq) and Compound 3A(4.19 g, 21.93 mmol, 1.5 eq) in DMF (50 mL) was added HATU (8.34 g,21.93 mmol, 1.5 eq) and DIEA (5.67 g, 43.86 mmol, 7.64 mL, 3 eq). Themixture was stirred at 20° C. for 3 hours. LCMS showed Compound E wasconsumed and desired mass was detected. The residue was poured intowater (500 mL) and extracted with ethyl acetate (150 mL×3). The combinedorganic phase was washed with brine (200 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The crude compound was usedinto the next step without further purification. Compound K (9 g, crude)was obtained as brown oil. LCMS: Retention time: 0.753 min, (M+H)=618.4.

Example 13: General procedure for preparation of5′-(4-fluorophenyl)-3′-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(compound 112)

To a mixture of Compound K (9 g, 14.57 mmol, 1 eq) in CH2Cl2 (2 mL) wasadded TFA (30.80 g, 270.12 mmol, 20.00 mL, 18.54 eq). The mixture wasstirred at 20° C. for 5 hours. LCMS showed Compound K was consumed anddesired mass was detected. The mixture was basified with saturatedNaHCO₃ to pH=8 and extracted with ethyl acetate (200 mL×4). The combinedorganic phase was washed with brine (100 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byreversed-phase HPLC (0.1% NH₃.H₂O). Compound 112 (3.04 g, 6.20 mmol,42.58% yield, 99.492% purity) was obtained as off-white solid, which waschecked with HNMR, LCMS, HPLC. LCMS: Retention time: 0.683 min,(M+H)=488.2. HPLC: Retention time: 1.157 min. HPLC: Retention time:1.155 min. HNMR: (400 MHz, DMSO-d₆) δ=13.14-12.98 (m, 1H), 9.72 (s, 1H),8.07 (s, 1H), 7.98 (s, 1H), 7.67 (d, J=9.2 Hz, 2H), 7.44-7.34 (m, 2H),7.14 (t, J=8.8 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 4.30-4.18 (m, 1H),3.13-3.04 (m, 4H), 2.47-2.42 (m, 4H), 2.22 (s, 3H), 1.40 (d, J=6.4 Hz,6H).

Example 14: Synthesis of Compound 113

4-(5′-(4-fluorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamido)benzoicacid (Compound 113) was synthesized under the same synthetic route asfor Compound 112 as white solid, which was determined by ¹HNMR, F NMR,LCMS and HPLC. LCMS: Retention time: 0.750 min, (M+H)=434.2. LCMS:Retention time: 0.760 min, (M+H)=434.2. HPLC: Retention time: 1.384 min.¹HNMR: (400 MHz, DMSO-d₆), δ=10.27 (s, 1H), 9.41 (s, 1H), 8.15 (s, 1H),7.91-7.81 (m, 4H), 7.45-7.39 (m, 2H), 7.30-7.21 (m, 2H), 4.46 (br d,J=6.6 Hz, 1H), 1.40 (d, J=6.8 Hz, 6H).

Example 15: Synthesis of Compound 111

5′-(4-fluorophenyl)-N-(4-(2-hydroxyethyl)phenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 111) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by ¹HNMR, F NMR, LCMSand HPLC. LCMS: Retention time: 0.745 min, (M+H)=434.3. LCMS: Retentiontime: 0.752 min, (M+H)=434.2. HPLC: Retention time: 1.472 min. HNMR:(400 MHz, DMSO-d₆), δ=13.08 (br s, 1H), 9.84 (s, 1H), 8.07 (s, 1H), 8.02(s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.44-7.36 (m, 2H), 7.19-7.10 (m, 4H),4.62 (t, J=5.2 Hz, 1H), 4.29-4.18 (m, 1H), 3.64-3.53 (m, 2H), 2.73-2.67(m, 2H), 1.40 (d, J=6.8 Hz, 6H).

Example 16: Synthesis of Compound 116

N-(4-(bis(2-hydroxyethyl)amino)phenyl)-5′-(4-fluorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 116) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by ¹HNMR, F NMR, LCMSand HPLC. LCMS: Retention time: 0.837 min, (M+H)=493.4. LCMS: Retentiontime: 0.790 min, (M+H)=493.1. HPLC: Retention time: 0.993 min. 1HNMR:(400 MHz, METHANOL-d₄), δ=9.53 (s, 1H), 8.19 (d, J=1.4 Hz, 1H), 8.07 (d,J=9.0 Hz, 2H), 7.71 (d, J=9.0 Hz, 2H), 7.56-7.40 (m, 2H), 7.36-7.20 (m,2H), 4.90-4.80 (m, 1H), 3.84 (br t, J=5.2 Hz, 4H), 3.66 (br s, 4H), 1.62(d, J=6.8 Hz, 6H).

Example 17: Synthesis of Compound 117

5′-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 117) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by ¹HNMR, F NMR, LCMSand HPLC. LCMS: Retention time: 0.839 min, (M+H)=518.4. LCMS: Retentiontime: 0.670 min, (M+H)=518.3. HPLC: Retention time: 1.484 min. ¹HNMR:(400 MHz, METHANOL-d₄), δ=9.13 (s, 1H), 7.98 (s, 1H), 7.66 (d, J=8.8 Hz,2H), 7.51-7.39 (m, 2H), 7.21 (t, J=8.8 Hz, 2H), 7.08 (d, J=9.2 Hz, 2H),4.82-4.74 (m, 1H), 3.96 (dd, J=4.6, 5.9 Hz, 2H), 3.91-3.58 (m, 4H),3.43-3.33 (m, 4H), 3.29-3.03 (m, 2H), 1.58 (d, J=6.6 Hz, 6H).

Example 18: Synthesis of Compound 99

N-(4-(4-carbamoylpiperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 99) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by ¹HNMR, F NMR, LCMSand HPLC. LCMS: Retention time: 1.298 min, (M+H)=474.2. HPLC: Retentiontime: 0.732 min. ¹H NMR (400 MHz, METHANOL-d₄) δ=8.06 (s, 1H), 7.89 (s,1H), 7.60 (br d, J=8.6 Hz, 2H), 7.38 (dd, J=5.5, 9.0 Hz, 2H), 7.10-6.95(m, 4H), 4.60-4.41 (m, 1H), 3.62-3.52 (m, 4H), 3.20-3.09 (m, 4H), 1.50(d, J=6.7 Hz, 6H). ¹⁹F NMR (376 MHz, METHANOL-d₄) δ=−116.70 (br s, 1F).

Example 19: Synthesis of Compound 97

5′-(4-fluorophenyl)-3′-isopropyl-N-(4-(4-sulfamoylpiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 97) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by ¹HNMR, F NMR, LCMSand HPLC. LCMS: Retention time: 0.956 min, (M+H)=553.3. HPLC: Retentiontime: 1.854 min. ¹H NMR (400 MHz, DMSO-d₆) δ=9.90-9.65 (m, 1H), 8.06 (s,1H), 7.99 (s, 1H), 7.69 (br d, J=8.2 Hz, 2H), 7.38 (dd, J=5.5, 9.0 Hz,2H), 7.13 (t, J=9.0 Hz, 2H), 6.94 (br d, J=9.0 Hz, 2H), 6.86 (br s, 2H),4.30-4.16 (m, 1H), 3.19 (br d, J=4.7 Hz, 4H), 3.09 (br d, J=5.1 Hz, 4H),1.39 (s, 3H), 1.38 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ=−115.64 (br s,1F).

Example 20: Synthesis of Compound 181

5′-(4-fluorophenyl)-3′-isopropyl-N-(4-(piperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 181) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by ¹HNMR, F NMR, LCMSand HPLC. LCMS: Retention time: 0.825 min, (M+H)=474.2. HPLC: Retentiontime: 0.693 min. ¹H NMR (400 MHz, DMSO-d₆) δ=9.76 (br s, 1H), 8.06 (s,1H), 7.99 (s, 1H), 7.67 (br d, J=8.2 Hz, 2H), 7.44-7.31 (m, 2H), 7.13(br t, J=9.0 Hz, 2H), 6.90 (br d, J=8.6 Hz, 2H), 4.30-4.14 (m, 1H), 3.09(br s, 4H), 2.95 (br s, 4H), 1.39 (br d, J=6.7 Hz, 6H). ¹⁹F NMR (376MHz, DMSO-d₆) δ=−115.66 (br s, 1F).

Example 22: Synthesis of Compound 119

5′-(4-fluorophenyl)-3′-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 119) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by ¹HNMR, F NMR, LCMSand HPLC. LCMS: Retention time: 0.851 min, (M+H)=460.4. HPLC: Retentiontime: 0.981 min. 1H NMR (400 MHz, DMSO-d₆) δ=12.97 (br s, 1H), 9.71 (s,1H), 8.04-7.80 (m, 2H), 7.66 (br d, J=8.7 Hz, 2H), 7.55-7.30 (m, 2H),7.14 (br t, J=8.9 Hz, 2H), 6.89 (br d, J=8.9 Hz, 2H), 3.59 (s, 3H),3.13-2.99 (m, 4H), 2.48-2.40 (m, 4H), 2.21 (s, 3H). ¹⁹F NMR (377 MHz,DMSO-d₆) δ=−115.52 (s, 1F).

Example 23: Synthesis of Compound 135

5′-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-3′-neopentyl-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 135) was synthesized under the same synthetic route as forCompound 102 as white solid, which was determined by ¹HNMR, LCMS andHPLC. LCMS: Retention time: 0.640 min, (M+H)=516.3. LCMS: Retentiontime: 0.715 min, (M+H)=516.3. HPLC: Retention time: 1.789 min. ¹HNMR:(400 MHz, DMSO-d₆), δ=10.05 (br d, J=2.2 Hz, 1H), 9.84 (s, 1H), 8.37 (s,1H), 7.99 (s, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.44 (dd, J=5.4, 8.8 Hz, 2H),7.22 (t, J=8.8 Hz, 2H), 7.00 (d, J=9.2 Hz, 2H), 4.07 (s, 2H), 3.79 (brd, J=12.2 Hz, 2H), 3.53 (br d, J=11.0 Hz, 2H), 3.17 (br s, 2H),3.00-2.82 (m, 5H), 0.72 (s, 9H).

Example 24: Synthesis of Compound 130

Example 25: General procedure for preparation of ethyl3′-(difluoromethyl)-5′-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3′H-[2,4′-biimidazole]-4-carboxylate(Compound BB)

To a solution of Compound AA 500 mg, 1.16 mmol, 1 eq) in ACN (5 mL) wasadded NaH (46.45 mg, 1.16 mmol, 60% purity, 1 eq) at 20° C. The mixturewas stirred at 20° C. for 1 hr. Dibromodifluoromethane (365.49 mg, 1.74mmol, 161.01 μL, 1.5 eq) and Zn (9.80 mg, 149.81 μmol, 1.29 e-1 eq) wasadded to the mixture at −15° C. The mixture was stirred at 20° C. for 16h. LCMS showed 42% of Compound BB was remained and 17% of desired masswas detected. The mixture was poured to aq NH₄Cl (10 mL). The mixturewas extracted with EA (20 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,PE:EA=5:1-0:1) to afford desired compound and 200 mg of reactant 1 wasrecovered. Compound BB (40 mg, 72.42 μmol, 6.24% yield, 87% purity) wasobtained as yellow oil, which was determined by LCMS. Ethyl5′-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3′H-[2,4′-biimidazole]-4-carboxylate(200 mg, 464.53 μmol, 40.00% yield) was recovered. LCMS: Retention time:0.958 min, (M+H)=481.3. LCMS: Retention time: 0.968 min, (M+H)=481.3.

3′-(difluoromethyl)-5′-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 130) was synthesized from BB under the same synthetic route asfor Compound 112 as oil, which was determined by ¹HNMR, LCMS and HPLC.LCMS: Retention time: 0.691 min, (M+H)=496.3. LCMS: Retention time:0.768 min, (M+H)=496.2. HPLC: Retention time: 2.175 min. 1HNMR: (400MHz, DMSO-d₆), δ=10.44 (br s, 1H), 9.83 (s, 1H), 8.51 (s, 1H), 8.14-7.78(m, 2H), 7.71 (d, J=9.2 Hz, 2H), 7.55-7.41 (m, 2H), 7.22 (t, J=8.9 Hz,2H), 7.00 (d, J=9.0 Hz, 2H), 3.76 (br s, 2H), 3.48 (br s, 2H), 3.19-3.11(m, 2H), 3.02 (br d, J=11.8 Hz, 2H), 2.83 (d, J=4.0 Hz, 3H).

Example 26: Synthesis of Compound 120

Example 27: General procedure for preparation of ethyl 2formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate(Compound M)

To a solution of Compound J (28 g, 80.16 mmol, 1 eq) in THF (300 mL) wasadded i-PrMgCl (2 M, 120.24 mL, 3 eq) at −40° C. The mixture was stirredat −40° C. for 10 min. To the mixture was added DMF (35.16 g, 480.97mmol, 37.01 mL, 6 eq) at −70° C. The mixture was stirred at 20° C. for 1hrs. LCMS showed desired mass was detected. The mixture was poured to 1NHCl (500 mL). The mixture was extracted with EA (300 mL×2). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography on silica gel (PE:EA=10:1-3:1). Compound M (15 g, 50.27mmol, 62.71% yield) was obtained as yellow oil, which was checked withHNMR. LCMS: Retention time: 0.955 min, (M+H)=299.2. HPLC: Retentiontime: 2.170 min. ¹HNMR: (400 MHz, CHLOROFORM-d) δ=8.03-7.95 (m, 1H),5.80 (s, 2H), 4.47-4.41 (m, 2H), 3.63-3.57 (m, 2H), 1.46-1.40 (m, 3H),0.99-0.93 (m, 2H), 0.00 (s, 8H).

Example 28: General procedure for preparation of ethyl5′-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3′H-[2,4′-biimidazole]-4-carboxylate(Compound N)

To a solution of Compound M (320 mg, 1.07 mmol, 1 eq) in THE (12 mL) wasadded NH₃.H₂O (582.40 mg, 4.15 mmol, 640.00 μL, 25% purity, 3.87 eq) at20° C. The mixture was stirred at 20° C. for 3.5 h. To the mixture wasadded Compound 1A (372.31 mg, 1.29 mmol, 1.2 eq) and DIEA (415.78 mg,3.22 mmol, 560.35 μL, 3 eq) at 20° C. The mixture was stirred at 20° C.for 1.5 h. LCMS showed Compound M was consumed and 31% of desired masswas detected. The mixture was poured to H₂O (20 mL). The mixture wasextracted with DCM (20 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,PE:EA=1:1-0:1) to afford desired compound. Compound N (330 mg, 490.54μmol, 45.74% yield, 64% purity) was obtained as yellow oil, which wasdetermined by LCMS. LCMS: Retention time: 0.803 min, (M+H)=431.3. LCMS:Retention time: 0.804 min, (M+H)=431.3.

Example 29: General procedure for preparation of ethyl5′-(4-fluorophenyl)-3′-(2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3′H-[2,4′-biimidazole]-4-carboxylate(Compound 0)

To a solution of ethyl Compound N (250 mg, 580.66 μmol, 1 eq) in DMF (5mL) was added K₂CO₃ (240.75 mg, 1.74 mmol, 3 eq) and Compound 2A (404.31mg, 1.74 mmol, 3 eq) at 20° C. The mixture was stirred at 20° C. for 16h. LCMS showed Compound N was consumed and 86% of desired mass wasdetected. The mixture was poured to H₂O (20 mL). The mixture wasextracted with DCM (20 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-TLC (PE:EA=1:1, productRf=0.5) to afford desired compound. Compound O (80 mg, 156.08 μmol,26.88% yield) was obtained as colorless oil. LCMS: Retention time: 0.976min, (M+H)=513.3.

Example 30: General procedure for preparation of5′-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-3′-(2,2,2-trifluoroethyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 120)

5′-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-3′-(2,2,2-trifluoroethyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 120) was synthesized from Compound O under the same syntheticroute as for Compound 112 as white solid, which was determined by ¹HNMR,LCMS and HPLC. LCMS: Retention time: 0.680 min, (M+H)=528.4. LCMS:Retention time: 0.747 min, (M+H)=528.2. HPLC: Retention time: 1.849 min.1HNMR: (400 MHz, DMSO-d₆), δ=9.83 (s, 2H), 8.09 (s, 1H), 7.95 (s, 1H),7.71 (d, J=9.0 Hz, 2H), 7.52-7.42 (m, 2H), 7.25-7.14 (m, 2H), 7.00 (d,J=9.2 Hz, 2H), 5.24 (br d, J=9.2 Hz, 2H), 3.80 (br d, J=12.7 Hz, 2H),3.54 (br s, 2H), 3.20-3.11 (m, 2H), 2.93 (br t, J=12.2 Hz, 2H), 2.87 (brs, 3H).

Example 31: Synthesis of Compound 167

Example 32: General procedure for preparation of5′-(4-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)-3′-(2,2,2-trifluoroethyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 167)

To a solution of2-[5-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)imidazol-4-yl]-N-[4-(4-methylpiperazin-1-yl)phenyl]-1H-imidazole-4-carboxamide (50 mg, 77.94 μmol, 1eq, TFA salt) in DCE (1 mL) was added 1-chloroethyl chloroformate (55.71mg, 389.69 μmol, 5 eq) and TEA (31.55 mg, 311.75 μmol, 43.39 μL, 4 eq),the mixture was stirred at 40° C. for 4 hrs. LCMS showed the reactant 1was consumed and a main peak was detected, then MeOH (1.5 mL) was addedto the reaction mixture, the mixture was stirred at 60° C. for 1 hr.LCMS showed 66% of desired mass was detected. The reaction mixture wasconcentrated in vacuum. The residue was purified with prep-HPLC (column:Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (10 mMNH₄HCO₃)−ACN]; B %: 12%-42%, 8 min). Compound 167 (2.99 mg, 5.24 μmol,6.72% yield, 90% purity) was obtained as an off-white solid. LCMS, HPLC,HNMR and FNMR confirmed the structure. LCMS: Retention time: 0.742 min,(M+H⁺)=310.5. LCMS: Retention time: 0.913 min, (M+H⁺)=514.4. LCMS:Retention time: 0.720 min, (M+H⁺)=514.1. HPLC: Retention time: 1.582min. 1H NMR: (400 MHz, METHANOL-d₄) δ=8.07 (s, 1H), 7.85 (s, 1H), 7.64(d, J=8.8 Hz, 2H), 7.50-7.37 (m, 2H), 7.15-6.99 (m, 4H), 5.20 (q, J=8.8Hz, 2H), 3.36-3.32 (m, 4H), 3.30-3.25 (m, 4H). ¹⁹F NMR: (377 MHz,METHANOL-d₄) δ=−73.58 (s, 1F).

Example 33: Synthesis of Compound 166

Example 34: General procedure for preparation of4-(4-(5′-(4-fluorophenyl)-3′-(2,2,2-trifluoroethyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamido)phenyl)-1-methylpiperazine1-oxide (Compound 166)

To a solution of2-[5-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)imidazol-4-yl]-N-[4-(4-methylpiperazin-1-yl)phenyl]-1H-imidazole-4-carboxamide (45 mg, 70.14 μmol, 1eq, TFA salt) in DCM (0.3 mL) was added m-CPBA (14.24 mg, 70.14 μmol,85% purity, 1 eq) and Pyridine (16.65 mg, 210.43 μmol, 16.98 μL, 3 eq)at 0° C., the mixture was stirred at 25° C. for 0.5 hr. LCMS showed 23%of desired mass was remained and 35% of desired mass was detected. Thereaction mixture was concentrated in vacuum. The residue was purifiedwith prep-HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobilephase: [water (10 mM NH₄HCO₃)−ACN]; B %: 10%-40%, 8 min). Compound 166(3.81 mg, 6.31 μmol, 8.99% yield, 89.98% purity) was obtained as a whitesolid. LCMS, HPLC, HNMR, and FNMR confirmed the structure. LCMS:Retention time: 0.632 min, (M+H⁺)=544.2. LCMS: Retention time: 0.777min, (M+H⁺)=544.3. HPLC: Retention time: 1.447 min. ¹HNMR: (400 MHz,METHANOL-d₄) δ=8.06 (s, 1H), 7.84 (s, 1H), 7.64 (d, J=9.0 Hz, 2H),7.49-7.39 (m, 2H), 7.16-7.00 (m, 4H), 5.19 (q, J=8.8 Hz, 2H), 3.71-3.58(m, 2H), 3.57-3.44 (m, 4H), 3.30-3.28 (m, 2H), 3.27 (s, 3H). ¹⁹F NMR:(377 MHz, METHANOL-d₄) δ=−73.57 (s, 1F).

Example 35: Synthesis of Compound 121

Example 36: General procedure for preparation of methyl5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxylate(Compound FF)

To a solution of Compound C (100 mg, 202.72 μmol, 1 eq) and Compound EE(83.12 mg, 405.44 μmol, 2 eq) in toluene (2 mL) was added methylChloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)(20 mg, 60.91 μmol, 0.3 eq) under N2 at 20° C. The mixture was stirredat 110° C. for 16 h. TLC showed Compound GG was consumed and a new spotwas detected. The mixture was concentrated in vacuo to afford residue.The residue was purified by prep-TLC (PE:EA=1:1) to afford desiredcompound. Compound FF (65 mg, 181.54 μmol, 89.55% yield, 91.7% purity)was obtained as colorless oil, which was determined by LCMS. LCMS:Retention time: 0.715 min, (M+H)=329.2.

Example 37: General procedure for preparation of5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)furan-2-carboxamide(121)

Compound 125 was synthesized from Compound FF under the same syntheticroute as for Compound 112 as oil, which was determined by ¹HNMR, LCMSand HPLC. LCMS: Retention time: 0.653 min, (M+H)=488.3. LCMS: Retentiontime: 0.718 min, (M+H)=488.3. HPLC: Retention time: 1.784 min. ¹H NMR:(400 MHz, DMSO-d₆),5=10.14 (s, 1H), 9.98-9.63 (m, 1H), 8.37 (br s, 1H),7.63 (d, J=8.8 Hz, 2H), 7.54-7.46 (m, 3H), 7.19 (t, J=8.8 Hz, 2H),7.04-6.97 (m, 3H), 4.27 (br d, J=6.4 Hz, 1H), 3.79 (br s, 2H), 3.53 (brd, J=11.4 Hz, 2H), 3.17 (br d, J=8.2 Hz, 2H), 2.93 (br s, 2H), 2.87 (s,3H), 1.45 (d, J=6.8 Hz, 6H).

Example 38: Synthesis of Compound 102

Example 39: Synthesis of Compound 132

5-(4-(5′-(4-fluorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamido)phenyl)pentanoic acid (Compound 132) was synthesized under the similarsynthetic route as for Compound 102 as white solid, which was determinedby HNMR, LCMS and HPLC. LCMS: Retention time: 0.747 min, [M+H⁺]=490.4.LCMS: Retention time: 0.801 min, [M+H⁺]=490.4. HPLC: Retention time:1.705 min. ¹H NMR: (400 MHz, DMSO-d₆), δ=9.85 (br s, 1H), 8.05 (s, 1H),8.01 (s, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.43-7.34 (m, 2H), 7.17-7.08 (m,4H), 4.29-4.18 (m, 1H), 2.58-2.52 (m, 2H), 2.19 (t, J=7.0 Hz, 2H),1.61-1.46 (m, 4H), 1.39 (d, J=6.7 Hz, 6H).

Example 40: Synthesis of Compound 126

5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(4-(2-hydroxyethyl)phenyl)furan-2-carboxamide (Compound 126) was synthesized under the samesynthetic route as for Compound 121 as white solid, which was determinedby HNMR, FNMR, LCMS and HPLC. LCMS: Retention time: 0.794 min,[M+H⁺]=434. LCMS: Retention time: 0.805 min, [M+H⁺]=434.1. HPLC:Retention time: 1.506 min. HPLC: Retention time: 1.494 min. ¹H NMR (400MHz, DMSO-d₆) δ=10.19 (s, 1H), 8.66 (s, 1H), 7.61 (d, J=8.4 Hz, 2H),7.56-7.47 (m, 3H), 7.28-7.14 (m, 4H), 7.01 (d, J=3.6 Hz, 1H), 4.33 (td,J=6.8, 13.2 Hz, 1H), 3.58 (s, 2H), 2.69 (t, J=7.0 Hz, 2H), 1.46 (d,J=6.8 Hz, 6H). ¹⁹F NMR (400 MHz, DMSO-d₆) δ=74.404.

Example 41: Synthesis of Compound 162

6-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)picolinamide (Compound 162) was synthesized underthe similar synthetic route as for Compound 121 as yellow solid, whichwas determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.913 min,[M+H⁺]=529.5. LCMS: Retention time: 0.923 min, [M+H⁺]=529.5. HPLC:Retention time: 1.992 min. 1H NMR: (400 MHz, DMSO-d₆), δ=10.23 (s, 1H),8.18-8.03 (m, 3H), 7.69 (d, J=9.0 Hz, 2H), 7.54 (dd, J=1.0, 7.8 Hz, 1H),7.41-7.34 (m, 2H), 7.10 (t, J=8.8 Hz, 2H), 6.94 (d, J=9.2 Hz, 2H),4.58-4.39 (m, 2H), 3.54 (q, J=6.0 Hz, 2H), 3.10 (br d, J=4.8 Hz, 4H),2.57 (br s, 4H), 2.46-2.41 (m, 2H), 1.44 (d, J=6.8 Hz, 6H).

Example 42: Synthesis of Compound 133

3-(4-(3′-isopropyl-5′-(4-(trifluoromethyl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamido)phenyl)propanoicacid (Compound 133) was synthesized under the similar synthetic route asfor Compound 102 as white solid, which was determined by HNMR, LCMS andHPLC. LCMS: Retention time: 0.752 min, (M+H)=512.2. LCMS: Retentiontime: 0.834 min, (M+H)=512.2, 5-95AB_R_220&254.lcm

HPLC: Retention time: 2.301 min. 1H NMR: (400 MHz, DMSO-d₆), δ=9.91 (s,1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.79-7.66 (m, 4H), 7.56 (d, J=8.2 Hz,2H), 7.18 (d, J=8.6 Hz, 2H), 4.38 (br d, J=6.6 Hz, 1H), 2.79 (t, J=7.6Hz, 2H), 2.53 (br s, 2H), 1.43 (d, J=6.8 Hz, 6H).

Example 43: Synthesis of Compound 137

3-(4-(5′-(4-chlorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamido)phenyl)propanoic acid (Compound 137) was synthesized under the similarsynthetic route as for Compound 102 as white solid, which was determinedby HNMR, LCMS and HPLC. LCMS: Retention time: 0.790 min, (M+H)=478.3.LCMS: Retention time: 0.788 min, (M+H)=478.3. HPLC: Retention time:1.644 min. ¹H NMR: (400 MHz, DMSO-d₆) δ=9.89 (s, 1H), 8.52 (br s, 1H),8.06 (s, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.45-7.40 (m, 2H), 7.39-7.34 (m,2H), 7.17 (d, J=8.4 Hz, 2H), 4.42-4.31 (m, 1H), 2.78 (t, J=7.6 Hz, 2H),2.54-2.52 (m, 2H), 1.42 (d, J=6.8 Hz, 6H).

Example 44: Synthesis of Compound 134

3-(4-(5′-(4-chlorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamido)phenyl)propanoic acid (Compound 134) was synthesized under the similarsynthetic route as for Compound 102 as yellow oil, which was determinedby HNMR, LCMS and HPLC. LCMS: Retention time: 0.671 min, (M+H)=568.3,5-95AB_R_220&254.lcm. LCMS: Retention time: 0.755 min, (M+H)=568.2.HPLC: Retention time: 1.869 min. ¹H NMR: (400 MHz, DMSO-d₆), δ=9.86 (s,1H), 9.71 (br s, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.71 (t, J=8.2 Hz,4H), 7.56 (d, J=8.2 Hz, 2H), 6.99 (d, J=9.2 Hz, 2H), 4.38-4.31 (m, 1H),3.83-3.71 (m, 4H), 3.60 (br d, J=11.2 Hz, 2H), 3.30-3.14 (m, 4H),3.10-2.94 (m, 2H), 1.43 (d, J=6.8 Hz, 6H).

Example 45: Synthesis of Compound 139

5′-(4-chlorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 139) was synthesized under the similar synthetic route as forCompound 137 as brown solid, which was determined by HNMR, LCMS andHPLC. LCMS: Retention time: 0.850 min, (M+H)=534.4. LCMS: Retentiontime: 0.713 min, (M+H)=534.4. HPLC: Retention time: 1.265 min. ¹H NMR:(400 MHz, DMSO-d₆) δ=9.84 (s, 1H), 9.67 (br d, J=3.6 Hz, 1H), 8.43 (s,1H), 8.03 (s, 1H), 7.70 (d, J=9.2 Hz, 2H), 7.48-7.29 (m, 4H), 6.98 (d,J=9.2 Hz, 2H), 4.37-4.27 (m, 1H), 3.80-3.75 (m, 4H), 3.32-3.14 (m, 6H),3.07-2.97 (m, 2H), 1.41 (d, J=6.8 Hz, 6H).

Example 46: Synthesis of Compound 146

5′-(3,4-difluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 146) was synthesized under the similar synthetic route as forCompound 102 as yellow solid, which was determined by HNMR, LCMS andHPLC. LCMS: Retention time: 0.717 min, [M+H⁺]=536.2. LCMS: Retentiontime: 0.627 min, [M+H⁺]=536.3. HPLC: Retention time: 1.252 min. ¹H NMR:(400 MHz, DMSO-d₆), δ=9.85 (s, 1H), 9.65 (br s, 1H), 8.28 (s, 1H), 8.04(s, 1H), 7.71 (d, J=9.2 Hz, 2H), 7.45-7.32 (m, 2H), 7.10 (ddd, J=1.8,4.2, 8.4 Hz, 1H), 6.98 (d, J=9.2 Hz, 2H), 4.32-4.21 (m, 1H), 3.77 (br d,J=5.0 Hz, 4H), 3.57 (brs, 2H), 3.29-3.16 (m, 4H), 3.07-2.96 (m, 2H),1.40 (d, J=6.8 Hz, 6H).

Example 47: Synthesis of Compound 158

5′-(4-fluorophenyl)-3′-((1r,4r)-4-hydroxycyclohexyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide (Compound158) was synthesized under the similar synthetic route as for Compound120 as white solid, which was determined by HNMR, LCMS and HPLC. LCMS:Retention time: 0.683 min, (M+H)=574.3. HPLC: Retention time: 1.600 min.¹H NMR: (400 MHz, DMSO-d₆), δ=9.85 (s, 2H), 8.76 (s, 1H), 8.06 (s, 1H),7.71 (d, J=9.0 Hz, 2H), 7.49-7.36 (m, 2H), 7.24 (t, J=8.9 Hz, 2H), 7.00(d, J=9.0 Hz, 2H), 4.03-3.95 (m, 1H), 3.82-3.72 (m, 4H), 3.60 (br d,J=9.9 Hz, 2H), 3.49-3.44 (m, 1H), 3.31-3.17 (m, 4H), 3.05 (br d, J=11.0Hz, 2H), 2.04-1.78 (m, 6H), 1.30-1.13 (m, 2H).

Example 48: Synthesis of Compound 156

5′-(3,4-difluorophenyl)-3′-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 156) was synthesized under the similar synthetic route as forCompound 102 as white solid, which was determined by HNMR, LCMS andHPLC. LCMS: Retention time: 0.886 min, (M+H)=506.4. LCMS: Retentiontime: 0.890 min, (M+H)=506.4. LCMS: Retention time: 0.713 min,(M+H)=506.2. HPLC: Retention time: 1.254 min. ¹H NMR: (400 MHz, DMSO-d₆)δ=9.73 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.66 (br d, J=8.8 Hz, 2H),7.42-7.31 (m, 2H), 7.08 (br d, J=1.6 Hz, 1H), 6.90 (br d, J=8.8 Hz, 2H),4.30-4.16 (m, 1H), 3.09 (br d, J=4.4 Hz, 4H), 2.52 (br s, 2H), 2.24 (s,3H), 2.07 (s, 2H), 1.39 (d, J=6.8 Hz, 6H).

Example 49: Synthesis of Compound 159

5′-(4-fluorophenyl)-3′-((1r,4r)-4-hydroxycyclohexyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 159) was synthesized under the similar synthetic route as for158 as yellow solid, which was determined by HNMR, LCMS and HPLC. LCMS:Retention time: 0.613 min, (M+H)=544.2. LCMS: Retention time: 0.690 min,(M+H)=544.3. HPLC: Retention time: 1.614 min. ¹H NMR: (400 MHz, DMSO-d₆)δ=9.81 (br s, 2H), 8.48-8.20 (m, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.72 (brd, J=8.8 Hz, 2H), 7.44-7.35 (m, 2H), 7.20-7.10 (m, 2H), 6.99 (br d,J=9.2 Hz, 2H), 3.79 (br d, J=13.2 Hz, 6H), 3.19-3.13 (m, 2H), 2.97-2.84(m, 6H), 1.99-1.82 (m, 6H), 1.17 (br d, J=12.4 Hz, 2H). HNMR: (400 MHz,DMSO-d₆+D20) 6=8.75-8.49 (m, 1H), 8.01 (d, J=1.2 Hz, 1H), 7.67 (br d,J=7.2 Hz, 2H), 7.47-7.32 (m, 2H), 7.28-7.09 (m, 2H), 6.99 (d, J=9.2 Hz,2H), 3.99-3.91 (m, 1H), 3.77 (br d, J=12.4 Hz, 2H), 3.55-3.44 (m, 3H),3.16 (br t, J=10.8 Hz, 2H), 3.00-2.84 (m, 5H), 2.06-1.77 (m, 6H),1.27-1.13 (m, 2H).

Example 50: Synthesis of Compound 142

3′-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-5′-(4-(trifluoromethyl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 142) was synthesized under the similar synthetic route as forCompound 102 as white solid, which was determined by HNMR, LCMS andHPLC. LCMS: Retention time: 0.678 min, (M+H)=538.3. LCMS: Retentiontime: 0.663 min, (M+H)=538.3. HPLC: Retention time: 1.889 min. ¹H NMR:(400 MHz, DMSO-d₆), δ=9.85 (s, 2H), 8.27 (s, 1H), 8.04 (s, 1H), 7.71(dd, J=8.8, 12.9 Hz, 4H), 7.56 (d, J=8.2 Hz, 2H), 6.99 (d, J=9.0 Hz,2H), 4.30 (br s, 1H), 3.79 (br d, J=13.2 Hz, 2H), 3.53 (br d, J=12.2 Hz,2H), 3.17 (br d, J=10.4 Hz, 2H), 3.09-2.78 (m, 5H), 1.42 (d, J=6.8 Hz,6H)

Example 51: Synthesis of Compound 150

5′-(4-chlorophenyl)-3′-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3′H-[4,4′-biimidazole]-2-carboxamide(Compound 150) was synthesized under the same synthetic route as forCompound 120 as white solid, which was determined by ¹H NMR, LCMS andHPLC. LCMS: Retention time: 0.714 min, [M+H⁺]=504.3. HPLC: Retentiontime: 1.992 min. ¹H NMR: (400 MHz, DMSO-d₆), δ=9.67 (br s, 1H), 8.05 (s,1H), 7.94 (s, 1H), 7.64 (br d, J=8.8 Hz, 2H), 7.44-7.30 (m, 4H), 6.89(d, J=9.1 Hz, 2H), 4.31-4.21 (m, 1H), 3.11-3.04 (m, 4H), 2.46-2.42 (m,4H), 2.21 (s, 3H), 1.38 (d, J=6.8 Hz, 6H).

Example 52: Synthesis of Compound 153

4-(4-(5′-(4-fluorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamido)phenyl)-1-methylpiperazine1-oxide (Compound 153) was synthesized under the same synthetic route asfor Compound 166 as white solid, which was determined by ¹HNMR, LCMS andHPLC. LCMS: Retention time: 0.782 min, (M+H)=504.5. LCMS: Retentiontime: 0.615 min, (M+H)=504.2. HPLC: Retention time: 1.225 min. ¹H NMR:1H NMR (400 MHz, DMSO-d₆) δ=9.85-9.61 (m, 1H), 8.05 (s, 1H), 7.97 (s,1H), 7.69 (br d, J=7.6 Hz, 2H), 7.41 (dd, J=6.0, 8.4 Hz, 2H), 7.18-7.08(m, 2H), 6.95 (d, J=9.2 Hz, 2H), 4.24 (td, J=6.8, 13.2 Hz, 1H),3.56-3.39 (m, 6H), 3.10 (s, 3H), 2.98 (br d, J=10.4 Hz, 2H), 1.40 (d,J=6.8 Hz, 6H).

Example 53: Synthesis of Compound 205

3′,5′-diisopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 205) was synthesized under the same synthetic route as forCompound 120 as white solid, which was determined by ¹HNMR, LCMS andHPLC. LCMS: Retention time: 0.853 min, [M+H⁺]=436.5. LCMS: Retentiontime: 0.850 min, [M+H⁺]=436.5. LCMS: Retention time: 0.863 min,[M+H⁺]=436.4. HPLC: Retention time: 1.605 min. ¹H NMR: (400 MHz,DMSO-d₆), δ=13.02-12.24 (m, 1H), 9.59 (br s, 1H), 7.89 (s, 1H), 7.78 (s,1H), 7.63 (br d, J=8.7 Hz, 2H), 6.89 (br d, J=9.0 Hz, 2H), 4.48-4.37 (m,1H), 3.13-3.05 (m, 4H), 2.92-2.83 (m, 1H), 2.47-2.41 (m, 4H), 2.21 (s,3H), 1.33 (d, J=6.7 Hz, 6H), 1.11 (d, J=6.8 Hz, 6H).

Example 54: Synthesis of Compound 196

5′-(4-fluorophenyl)-3′-isopropyl-N-(4-(3,4,5-trimethylpiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 196) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by ¹HNMR, LCMS andHPLC. LCMS: Retention time: 0.965 min, [M+H⁺]=516.4. LCMS: Retentiontime: 0.711 min, [M+H⁺]=516.4. HPLC: Retention time: 1.075 min,10-80AB_4 min.lcm, EW25973-78-P1A6. ¹H NMR: (400 MHz, DMSO-d₆)δ=13.28-12.82 (m, 1H), 9.69 (br s, 1H), 8.05 (s, 1H), 7.97 (s, 1H), 7.66(br d, J=8.0 Hz, 2H), 7.39 (dd, J=5.6, 8.7 Hz, 2H), 7.13 (t, J=8.9 Hz,2H), 6.89 (br d, J=8.9 Hz, 2H), 4.38-4.17 (m, 1H), 3.50 (br d, J=10.9Hz, 2H), 2.39-2.31 (m, 2H), 2.29-2.14 (m, 5H), 1.39 (d, J=6.7 Hz, 6H),1.07 (d, J=5.9 Hz, 6H).

Example 55: Synthesis of Compound 185

5′-(4-fluorophenyl)-3′-isopropyl-N-(4-(4-methyl-3-oxopiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 185) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by 1HNMR, LCMS andHPLC. LCMS: Retention time: 0.846 min, (M+H)=502.5. LCMS: Retentiontime: 0.763 min, (M+H)=502.2. HPLC: Retention time: 1.499 min. ¹H NMR:(400 MHz, DMSO-d₆) δ=13.18-12.93 (m, 1H), 9.76 (s, 1H), 8.07 (s, 1H),7.99 (s, 1H), 7.71 (d, J=9.2 Hz, 2H), 7.44-7.33 (m, 2H), 7.20-7.07 (m,2H), 7.00-6.85 (m, 2H), 4.29-4.18 (m, 1H), 3.71 (s, 2H), 3.46-3.40 (m,4H), 2.90 (s, 3H), 1.40 (d, J=6.8 Hz, 6H).

Example 56: Synthesis of Compound 188

N-(4-(4-acetylpiperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 188) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by ¹HNMR, LCMS andHPLC. LCMS: Retention time: 0.851 min, [M+H⁺]=516.5. LCMS: Retentiontime: 0.756 min, [M+H⁺]=516.1. HPLC: Retention time: 1.475 min. ¹H NMR:(400 MHz, DMSO-d₆), δ=13.03 (br s, 1H), 9.74 (s, 1H), 8.05 (s, 1H), 7.98(s, 1H), 7.69 (br d, J=8.8 Hz, 2H), 7.42-7.33 (m, 2H), 7.13 (t, J=8.9Hz, 2H), 6.93 (br d, J=8.8 Hz, 2H), 4.29-4.17 (m, 1H), 3.57 (br d, J=3.7Hz, 4H), 3.14-3.08 (m, 2H), 3.06-3.00 (m, 2H), 2.04 (s, 3H), 1.39 (d,J=6.7 Hz, 6H).

Example 57: Synthesis of Compound 189

5′-(4-fluorophenyl)-3′-isopropyl-N-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 189) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by 1HNMR, LCMS andHPLC. LCMS: Retention time: 0.726 min, (M+H)=556.3. LCMS: Retentiontime: 0.805 min, (M+H)=556.3. HPLC: Retention time: 1.635 min. HNMR:(400 MHz, DMSO-d₆), δ=9.84 (s, 1H), 8.88 (br s, 1H), 8.07 (s, 1H), 7.68(d, J=8.8 Hz, 2H), 7.51-7.38 (m, 2H), 7.32-7.21 (m, 2H), 6.99 (br d,J=8.8 Hz, 2H), 4.45 (s, 1H), 3.30 (d, J=10.2 Hz, 2H), 3.22-3.12 (m, 4H),2.89-2.76 (m, 4H), 1.45 (d, J=6.8 Hz, 6H).

Example 58: Synthesis of Compound 186

5′-(4-fluorophenyl)-3′-isopropyl-N-(4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 186) was synthesized under the same synthetic route as forCompound 112 as white solid, which was determined by ¹HNMR, LCMS andHPLC. LCMS: Retention time: 0.635 min, (M+H)=514.3. LCMS: Retentiontime: 0.712 min, (M+H)=514.3. HPLC: Retention time: 1.285 min. HNMR:(400 MHz, DMSO-d₆), δ=8.77 (s, 1H), 8.03 (s, 1H), 7.65 (br d, J=9.0 Hz,2H), 7.48-7.35 (m, 2H), 7.23 (t, J=8.8 Hz, 2H), 6.90 (d, J=9.2 Hz, 2H),4.40 (s, 1H), 4.04 (br s, 2H), 3.78-3.70 (m, 2H), 3.06 (br d, J=12.0 Hz,2H), 2.77 (s, 3H), 2.26-2.15 (m, 2H), 2.00 (br d, J=8.2 Hz, 2H), 1.43(d, J=6.8 Hz, 6H).

Example 59: Synthesis of Compound 190

5′-(4-fluorophenyl)-3′-(2,2,2-trifluoroethyl)-N-(4-(3,4,5-trimethylpiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 190) was synthesized under the same synthetic route as forCompound 120 as white solid, which was determined by ¹HNMR, LCMS andHPLC. LCMS: Retention time: 0.937 min, (M+H)=556.5. HPLC: Retentiontime: 1.519 min. ¹H NMR: (400 MHz, CHLOROFORM-d) δ=8.75 (s, 1H), 7.74(br d, J=14.3 Hz, 2H), 7.60 (br d, J=8.4 Hz, 2H), 7.52-7.47 (m, 2H),7.12 (br t, J=7.5 Hz, 2H), 6.96 (br d, J=8.7 Hz, 2H), 5.14-5.07 (m, 2H),3.47 (br d, J=11.2 Hz, 2H), 2.61 (br t, J=11.0 Hz, 2H), 2.44 (br s, 2H),2.36 (s, 3H), 1.21 (d, J=6.1 Hz, 6H).

Example 60: Synthesis of Compound 194

5′-(4-fluorophenyl)-N-(4-(4-methyl-3-oxopiperazin-1-yl)phenyl)-3′-(2,2,2-trifluoroethyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 194) was synthesized under the same synthetic route as forCompound 120 as white solid, which was determined by ¹HNMR, LCMS andHPLC. LCMS: Retention time: 0.832 min, (M+H)=542.4. HPLC: Retentiontime: 1.704 min. ¹H NMR: (400 MHz, CHLOROFORM-d) δ=8.78 (s, 1H), 7.76(d, J=12.5 Hz, 2H), 7.65 (d, J=9.0 Hz, 2H), 7.53-7.49 (m, 2H), 7.13 (t,J=8.7 Hz, 2H), 6.94 (d, J=9.0 Hz, 2H), 5.12 (q, J=8.4 Hz, 2H), 3.87 (s,2H), 3.50 (s, 4H), 3.06 (s, 3H).

Example 61: Synthesis of Compound 191

N-(4-(4-acetylpiperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-(2,2,2-trifluoroethyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 191) was synthesized under the same synthetic route as forCompound 120 as white solid, which was determined by 1HNMR, LCMS andHPLC. LCMS: Retention time: 0.847 min, (M+H)=556.5. HPLC: Retentiontime: 1.706 min. ¹H NMR: (400 MHz, CHLOROFORM-d) δ=9.67 (br s, 1H), 8.79(s, 1H), 7.77-7.71 (m, 2H), 7.63 (d, J=8.9 Hz, 2H), 7.52-7.47 (m, 2H),7.12 (t, J=8.6 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 5.10 (q, J=8.5 Hz, 2H),3.81-3.76 (m, 2H), 3.67-3.63 (m, 2H), 3.21-3.17 (m, 2H), 3.17-3.13 (m,2H), 2.15 (s, 3H).

Example 62: Synthesis of Compound 192

5′-(4-fluorophenyl)-3′-(2,2,2-trifluoroethyl)-N-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 192) was synthesized under the same synthetic route as forCompound 120 as white solid, which was determined by 1HNMR, LCMS andHPLC. LCMS: Retention time: 0.943 min, (M+H)=596.5. HPLC: Retentiontime: 1.965 min. ¹H NMR: (400 MHz, CHLOROFORM-d) δ=9.78 (br d, J=0.7 Hz,1H), 8.76 (s, 1H), 7.70 (d, J=14.1 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.47(dd, J=5.6, 8.2 Hz, 2H), 7.10 (t, J=8.6 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H),5.08 (q, J=8.4 Hz, 2H), 3.24-3.20 (m, 4H), 3.07 (q, J=9.6 Hz, 2H),2.89-2.86 (m, 4H).

Example 63: Synthesis of Compound 193

5′-(4-fluorophenyl)-N-(4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-3′-(2,2,2-trifluoroethyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound 193) was synthesized under the same synthetic route as forCompound 120 as white solid, which was determined by ¹HNMR, LCMS andHPLC. LCMS: Retention time: 1.036 min, (M+H)=554.5. HPLC: Retentiontime: 1.544 min, 10-80AB_4 min.lcm. 1H NMR: (400 MHz, CHLOROFORM-d)δ=8.73 (br s, 1H), 7.71 (br d, J=14.4 Hz, 2H), 7.55 (br d, J=8.6 Hz,2H), 7.48 (br dd, J=5.9, 7.4 Hz, 2H), 7.09 (br t, J=8.3 Hz, 2H), 6.81(br d, J=8.8 Hz, 2H), 5.05 (br d, J=7.7 Hz, 2H), 4.76 (s, 1H), 3.35 (brd, J=9.7 Hz, 2H), 3.26 (br s, 2H), 3.00 (br d, J=10.5 Hz, 2H), 2.34 (s,3H), 2.07-2.02 (m, 2H), 1.81 (br d, J=7.6 Hz, 2H).

Certain compounds of Table 1 can be prepared employing alternativereagents in the examples above. Exemplary compounds may include, but arenot limited to, a compound or salt thereof selected from Table 1 whichmay be prepared using the examples above and the accompanying proceduresdescribed herein.

TABLE 1 Compounds and Assay Data Human Liver TNIK MAP4K4 CompoundMicrosome (IC50, (IC50, # Compound Structure (μM/min/mg) nM) nM) 172

+++ ++ 175

+++ 128

+ +++ +++ 186

+++ +++ 131

+++ +++ ++ 127

+ +++ +++ 125

++ +++ +++ 188

+++ ++ 159

++ +++ ++ 158

+++ +++ ++  97

+ ++ ++ 121

+ +++ ++ 196

++ ++ 193

++ ++ 112

++ ++ ++ 181

++ ++ ++ 126

+ ++ ++ 117

++ ++ ++ 132

+++ ++ ++ 189

++ ++ 116

+++ ++ ++ 153

+++ ++ ++ 190

+++ ++ 185

++ ++ 191

++ ++ 167

++ ++ + 111

++ ++ + 156

++ ++ + 194

++ + 146

++ ++ + 102

+++ ++ + 150

++ ++ +  99

++ + + 166

+++ + + 139

++ ++ + 120

++ ++ + 113

+++ +++ + 192

++ + 135

+ ++ + 119

++ + + 137

+++ +++ + 130

++ ++ + 142

+ + + 134

++ + + 133

+++ + + 164

168

171

198

199

200

205

Example 64: Metabolic Stability in Human and Mouse Liver Microsomes

TABLE 1.1 Compound Information Compound Compound Batch Exact Stock No.ID No. Mass Concentration (mM) 172 172 10 Control Testosterone 288.42 10Control Diclofenac 295.14 10 Control Propafenone 341.44 10

2.1. Test Compound and Control Working Solution Preparation: Workingsolution: 5 μL of compound and control stock solution (10 mM in dimethylsulfoxide (DMSO)) were diluted with 495 μL of acetonitrile (ACN)(intermediate solution concentration: 100 μM, 9900 ACN).

2.2. NADPH Cofactor Preparation

2.2.1. Materials: NADPH powder: β-Nicotinamide adenine dinucleotidephosphate reduced form, tetrasodium salt; NADPH.4Na (Vendor: Chem-ImpexInternational, Cat. No. 00616).

2.2.2. Preparation Procedure: The appropriate amount of NADPH powder wasweighed and diluted into a 10 mM MgCl₂ solution (working solutionconcentration: 10 unit/mL; final concentration in reaction system: 1unit/mL).

2.3. Liver Microsomes Preparation:

2.3.1. Materials:

TABLE 2.1 Liver Microsomes Information Product Species InformationVendor Abbreviation Human Cat No. 452117 Corning HLM Lot No. 38295 CD-1Cat No. M00501 BioIVT MLM Mouse Lot No. WQP

2.3.2. Preparation Procedure: The appropriate concentrations ofmicrosome working solutions were prepared in 100 mM potassium phosphatebuffer.

2.4. Stop Solution Preparation: Cold (4° C.) acetonitrile (ACN)containing 200 ng/mL tolbutamide and 200 ng/mL labetalol as internalstandards (IS) was used as the stop solution.

2.5. Assay Procedure:

2.5.1. Pre-warm empty ‘Incubation’ plates T60 and NCF60 for 10 minminutes.

2.5.2. Dilute liver microsomes to 0.56 mg/mL in 100 mM phosphate buffer.

2.5.3. Transfer 445 μL microsome working solutions (0.56 mg/mL) intopre-warmed ‘Incubation’ plates T60 and NCF60, Then pre-incubate‘Incubation’ plates T60 and NCF60 for 10 min at 37° C. with constantshaking. Transfer 54 μL liver microsomes to blank plate, then add 6 μLNAPDH cofactor to blank plate, and then add 180 μL quenching solution toblank plate.

2.5.4 Add 5 μL compound working solution (100 μM) into ‘incubation’plates (T60 and NCF60) containing microsomes and mix 3 times thoroughly.

2.5.5. For the NCF60 plate, add 50 μL of buffer and mix 3 timesthoroughly. Start timing; plate will be incubated at 37° C. for 60 minwhile shaking.

2.5.6. In ‘Quenching’ plate TO, add 180 μL quenching solution and 6 μLNAPDH cofactor. Ensure the plate is chilled to prevent evaporation.

2.5.7. For the T60 plate, mix 3 times thoroughly, and immediately remove54 μL mixture for the 0-min time point to ‘Quenching’ plate. Then add 44μL NAPDH cofactor to incubation plate (T60). Start timing; plate will beincubated at 37° C. for 60 min while shaking.

TABLE 2.2 Final Concentration of Each Component in Incubation MediumComponent Concentration Microsome 0.5 mg protein/mL Test Compound 1 μMControl Compound 1 μM Acetonitrile 0.99% DMSO 0.01%

2.5.8. At 5, 10, 20, 30, and 60 min, add 180 μL quenching solution to‘Quenching’ plates, mix once, and serially transfer 60 μL sample fromT60 plate per time point to ‘Quenching’ plates.

TABLE 2.3 Reaction Plates Incubation Time Point Start Time End TimeBlank 1:00:00 0:00:00 T60 1:00:00 0:00:00 T30 0:30:00 0:00:00 T200:20:00 0:00:00 T10 0:10:00 0:00:00 T5 0:05:00 0:00:00 T0 mix 3 timesand out to ‘Quenching’ plate

2.5.9. For NCF60: mix once, and transfer 60 μL sample from the NCF60incubation to ‘Quenching’ plate containing quenching solution at the60-min time point.

TABLE 2.4 NCF60 Incubation Time Point Start Time End Time NCF60 1:00:000:00:00

2.5.10. All sampling plates are shaken for 10 min, then centrifuged at4000 rpm for 20 minutes at 4° C.

2.5.11. Transfer 80 μL supernatant into 240 μL HPLC water, and mix byplate shaker for 10 min.

2.5.12. Each bioanalysis plate was sealed and shaken for 10 minutesprior to LC-MS/MS analysis.

3.1. The equation of first order kinetics was used to calculate T½ andIntrinsic clearance (CLint mic) in (μL/min/mg).

Equation of first order kinetic.

${C_{t} = {{C_{0} \cdot c^{{- k_{e}} \cdot 1}}{when}}}{{C_{t} = {\frac{1}{2}C_{0}}},{T_{1/2} = {\frac{{Ln}2}{k_{e}} = \frac{0.693}{k_{e}}}}}{{CL}_{in{t({mic})}} = {\frac{0.693}{{In}{vitro}T_{1/2}} \cdot \frac{1}{{mg}/{mL}{microsomal}{protein}{in}{reaction}{system}}}}{{CL}_{in{t({lixer})}} = {{CL}_{in{t({mic})}} \cdot \frac{{mg}{microsomes}}{g{liver}} \cdot \frac{g{liver}}{{kg}{body}{weight}}}}$

Table 1 include M/min/mg values of selected compounds, compounds havinga LM Clint of μM/min/mg of 1-10 μM/min/mg as +++, 10-100 μM/min/mg as++, and >100 μM/min/mg as

Example 65: TNIK Human STE Kinase Enzymatic Radiometric Assay

Assay Information

ASSAY TYPE: Biochemical

ASSAY SUB TYPE: Enzymatic

FUNCTIONAL MODE: Antagonist

DETECTION METHOD: Radiometric

MEASURED RESPONSE: Scintillation

PROCEDURE SUMMARY: TNIK(h) is incubated with 8 mM MOPS pH 7.0, 0.2 mMEDTA, 250 μM RLGRDKYKTLRQIRQ, 10 mM Magnesium Acetate and[gamma-33P-ATP](specific activity and concentration as required). Thereaction is initiated by the addition of the Mg/ATP mix. Afterincubation for 40 minutes at room temperature, the reaction is stoppedby the addition of phosphoric acid to a concentration of 0.5%. 10 ul ofthe reaction is then spotted onto a P30 filter mat and washed four timesfor 4 minutes in 0.425% phosphoric acid and once in methanol prior todrying and scintillation counting.

SUBSTRATE: 250 μM RLGRDKYKTLRQI

TRACER: 33P

ATP CONCENTRATION: 70 μM

INCUBATION: 40 min at Room temperature

CONTROL INHIBITOR: 1-NM-PP1

COMPOUND CONCENTRATION: 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01μM, 0.003 μM, 0.001 μM

COMPOUND DILUTION SCHEME: All compounds supplied were prepared to aworking stock of 50× final assay concentration in 100% DMSO. Whereappropriate, more concentrated stocks were diluted manually to 50× using100% DMSO. Compounds supplied as powders were reconstituted to a 10 mMstock in 100% DMSO before further dilution to 50×.ASSAY PROCEDURE: The required volume of the 50× stock of test compoundwas added to the assay before a reaction mix containing the enzyme andsubstrate was added. The reaction was initiated by the addition of ATPat the selected concentration. There was no pre-incubation of thecompound with the enzyme/substrate mix prior to ATP addition. Forfurther details of each individual assay, please refer to the website orthe accompanying protocol document.DATA ANALYSIS: Data are handled using a custom built in-house analysissoftware. Results are expressed as kinase activity remaining, as apercentage of the DMSO control. This is calculated using the followingformula:

$\frac{{{Mean}{of}{Sample}{Counts}} - {{Mean}{of}{Blank}{Counts}}}{{Mean}{of}{Control}{Counts}}$

For IC50 determinations, data are analyzed using XLFit version 5.3 (IDBusiness Solutions).

Sigmoidal dose-response (variable slope) curves are fit based on themean result for each test concentration using non-linear regressionanalysis. Where the top and/or bottom of the curve fall >10% out with100 and 0, respectively, either or both of these limits may beconstrained at 100 and 0, provided that the QC criterion on R² is met.

Table 1 include IC₅₀ values for TNIK of selected compounds; compoundshaving an IC50 value of 1-12 nM as +++, 12-120 nM as ++, and >120 nM as+. The IC₅₀ values can be found in Table 1.

Example 66: MAP4K4 Human STE Kinase Enzymatic Radiometric Assay

ASSAY TYPE: Biochemical

ASSAY SUB TYPE: Enzymatic

FUNCTIONAL MODE: Antagonist

DETECTION METHOD: Radiometric

MEASURED RESPONSE: Scintillation

PROCEDURE SUMMARY: MAP4K4 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mMEDTA, 250 μM RLGRDKYKTLRQIRQ, 10 mM Magnesium Acetate and[gamma-33P-ATP](specific activity and concentration as required). Thereaction is initiated by the addition of the Mg/ATP mix. Afterincubation for 40 minutes at room temperature, the reaction is stoppedby the addition of phosphoric acid to a concentration of 0.5%. 10 ul ofthe reaction is then spotted onto a P30 filter mat and washed four timesfor 4 minutes in 0.425% phosphoric acid and once in methanol prior todrying and scintillation counting.

SUBSTRATE: 250 μM RLGRDKYKTLRQI

TRACER: 33P

ATP CONCENTRATION: 200 μM

INCUBATION: 40 min at Room temperature

CONTROL INHIBITOR: Staurosporine

COMPOUND CONCENTRATION: 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01μM, 0.003 μM, 0.001 μM.

COMPOUND DILUTION SCHEME: All compounds supplied were prepared to aworking stock of 50× final assay concentration in 100% DMSO. Whereappropriate, more concentrated stocks were diluted manually to 50× using100% DMSO. Compounds supplied as powders were reconstituted to a 10 mMstock in 100% DMSO before further dilution to 50×.

ASSAY PROCEDURE: The required volume of the 50× stock of test compoundwas added to the assay before a reaction mix containing the enzyme andsubstrate was added. The reaction was initiated by the addition of ATPat the selected concentration. There was no pre-incubation of thecompound with the enzyme/substrate mix prior to ATP addition. Forfurther details of each individual assay, please refer to the website orthe accompanying protocol document.

DATA ANALYSIS: Data are handled using a custom built in-house analysissoftware. Results are expressed as kinase activity remaining, as apercentage of the DMSO control. This is calculated using the followingformula:

$\frac{{{Mean}{of}{Sample}{Counts}} - {{Mean}{of}{Blank}{Counts}}}{{Mean}{of}{Control}{Counts}}$

For IC₅₀ determinations, data are analyzed using XLFit version 5.3 (IDBusiness Solutions). Sigmoidal dose-response (variable slope) curves arefit based on the mean result for each test concentration usingnon-linear regression analysis. Where the top and/or bottom of the curvefall >10% out with 100 and 0, respectively, either or both of theselimits may be constrained at 100 and 0, provided that the QC criterionon R2 is met.

Table 1 include IC₅₀ values for MAP4K4 of selected compounds; compoundshaving an IC50 value of 1-12 nM as +++, 12-120 nM as ++, and >120 nM as+.

Example 67: Masson's Trichrome (M&T) Staining and Ashcroft Score

Masson's Trichrome (M&T) Staining Protocol:

Lung sections were cut at 4 m in thickness, dried in an oven for 1 hour,and stained with M&T by a standard staining protocol. The sections werebriefly stained with Weigert's iron hematoxylin working solution for 10minutes. This was followed by staining in Biebrich scarlet-acid fuchsinsolution for 10 minutes and differentiation inphosphomolybdic-phosphotungstic acid solution for 5 minutes or untilcollagen is not red. The sample was then transferred to aniline bluesolution and stained for 1 minute followed by dedifferentiation in 100acetic acid solution. This was followed by dehydration and placement ofa cover-slip for the subsequent image analysis.

For image analysis of collagen deposition, Masson's trichrome stainedslides were scanned using Aperio Scan Scope Model: CS2 (Leica), at 200×magnification. The area of fibrosis stained with Masson's trichromestain was quantified with the HALO® image analysis platform from IndicaLabs. The whole left lung section was selected as an annotation layer.

Fibrotic modifications were assessed morphologically andsemi-quantitatively graded according to the scale of 0-8 defined byAshcroft et al. and modified by Hübner et al. as described in the Table3 below. The final score was expressed as a mean of individual scoresobserved across all microscopic fields.

TABLE 3 Modified Ashcroft Score. Score Characterization ModifiedAshcroft Score 0 Alveolar septa: No fibrotic burden at the flimsiestsmall fibers in some alveolar walls Lung structure: Normal lung 1Alveolar septa: Isolated gentle fibrotic changes (septum ≤3× thickerthan normal) Lung structure: Alveoli partly enlarged and rarefied, butno fibrotic masses present 2 Alveolar septa: Clearly fibrotic changes(septum >3× thicker than normal) with knot-like formation but notconnected to each other Lung structure: Alveoli partly enlarged andrarefied, but no fibrotic masses 3 Alveolar septa: Contiguous fibroticwalls (septum >3× thicker than normal) predominantly in wholemicroscopic field Lung structure: Alveoli partly enlarged and rarefied,but no fibrotic masses 4 Alveolar septa: Variable Lung structure: Singlefibrotic masses (≤10% of microscopic field) 5 Alveolar septa: VariableLung structure: Confluent fibrotic mass (>10% and ≤50% of micro- scopicfield). Lung structure severely damaged but still preserved 6 Alveolarsepta: Variable, mostly not existent Lung structure: Large contiguousfibrotic masses (>50% of micro- scopic field). Lung architecture mostlyno preserved 7 Alveolar septa: non-existent Lung structure: Alveolinearly obliterated with fibrous masses but still up to five air bubbles8 Alveolar septa: non-existent Lung structure: Microscopic fieldcomplete obliteration with fibrotic masses

Example 68: Alpha-SMA IHC Assay

Protocol:

For immunohistochemical staining, 4 m thick-sections were placed onslides and after overnight drying, the paraffin was removed with xylene.The sections were placed in a graded ethanol series and immersed indistilled water. After heat-induced Citrate antigen (pH=6.0) unmasking,the sections were immersed in 3% hydrogen peroxide solution for 5 mins.To avoid nonspecific staining, the sections were then incubated inblocking serum for 15 mins at room temperature, followed by addition ofprimary rabbit polyclonal anti-α-SMA antibodies in a dilution 1:400 for1 hour. This was followed by the addition of secondary goat polyclonalantibodies conjugated to HRP.

For image analysis of fibrosis, α-SMA stained sections were scanned viaAperio CS2 Scan machine. The area of fibrosis were quantified with theHALO® image analysis platform from Indica Labs. The whole left lungsection was selected as an annotation layer. The bronchus was excludedin the annotation layer. The area occupied by collagen fibers wasmeasured using “Area Quantification v2.1.3” module. The percentage ofpositive areas in the selected annotation was then calculated by theprogram. The fibrosis was expressed as percentage per lung section.

Example 69: Bleomycin-Induced Lung Fibrosis Mouse Model

Protocol:

Eight-week-old C57BL/6 male mice were anaesthetized with Pentobarbital(60 mg/kg body weight, i.p.) and received bleomycin on day 1 at a doseof 0.66 mg/kg (equivalent to 1 U/kg) by intra-tracheal administration.Compound treatment started on day 7 after the induction of lung fibrosiswhen the initial lung injury and inflammation were already abating.

Example 70: Bleomycin-Induced Rat Model for Skin Fibrosis

Protocol:

Five to six-week-old Sprague Dawley male rats were transientlyanesthetized using isoflurane and their dorsal regions were shaved usinga Wahl pet trimmer. Bleomycin (BLM) will be diluted to 1 mg/ml withsterile phosphate-buffered saline (PBS). Using a 1 ml syringe containinga 27-gauge needle, 100 μl of BLM solution will be injectedsubcutaneously into two sites on the shaved regions, once daily for 4weeks. Naive controls will be injected daily with an equivalent volumeof sterile PBS.

Example 71: Unilateral Ureteral Obstruction Renal Fibrosis Model

Protocol:

On Day 0, UUO surgery was performed onto seven-week-old female C57BL/6mice under three types of mixed anesthetic agents (medetomidine,midazolam, butorphanol). After shaving the hair, the abdomen was cutopen and the left ureter will be exteriorized. The ureter was ligated4-0 silk sutures at two points. The peritoneum and the skin were closedwith sutures, and the mice were transferred to a clean cage and keptuntil recovery from anesthesia. Mice were divided into two slots basedon their body weight before the day of the surgery. Compounds wereadministered orally from Day 0 to 13. On Day 14. The ligated left kidneyand right kidney weight were measured at sacrifice.

Example 72: Collagen and Alpha-SMA in LX-2

Method:

Culture medium was prepared with DMEM supplemented with 2% FBS and 1%P/S. The medium was removed from culture flask containing the confluentlayer of LX-2 cells. 3 ml of 0.25% Trypsin-EDTA solution was then addedand cells were incubated at 37° C. for 5 min for each T150-flask. 7 mlof culture medium was added to stop trypsinization. The cells werecentrifuged at 300×g for 5 min. Supernatant medium was discarded andcells were re-suspended with fresh culture medium. The cells werecounted with Cell viability analyzer. 5.0E+05 cells/well were seededinto 6-well plate containing 2.0 mL of culture medium. The cells werecultured overnight at 37° C. The next day, the complete medium wasreplaced with medium with 0.4% FBS for starvation. After 24 h incubationin medium with reduced serum, LX-2 cells were treated with compounds (8concentrations, 3-fold dilution) in duplicate for 30 minutes beforebeing stimulated with 4 ng/ml of TGF-β for additional 48 hours. Inparallel, medium containing only DMSO and TGF-β was used as blankcontrol and positive control, respectively. TGF-β induction was used asmaximum induction positive control. The culture medium was discarded atthe end of induction. Cells were washed once using ice-cold DPBS. RIPAbuffer was added to lyse the cells for 20 min. The cells were thenscraped off the culture plate, collected in a tube and centrifuged. Thesupernatant was stored at −80° C. The total amount of protein in thelysate was determined using BCA Protein Assay kit. The cell treatment offibrosis assay was performed in three independent experiments for eachcompound.

All the lysate samples were adjusted to the same protein concentrationwith RIPA buffer after BCA assay. The samples with the same proteinamount were mixed with 4×LDS sample buffer and boiled at 95° C. for 5min. The denatured samples were used for electrophoresis. Western blotwas performed according to the standard protocols. The same volume ofprotein was loaded onto 4-12% Bis-Tris gel. Duplicate lysates of sampleswere loaded onto two gels. The gels were run for 0.5 h at 80 V and 120 Vfor another 1 h. When the electrophoresis was completed, the gelscontaining target protein Collagen I (COL1A1) were transferred onto NCmembrane using Trans-Blot Electrophoretic Transfer Cell for 90 min at100 V. The iBlot™ 2 Gel Transfer Device was used to transfer α-SMA andGAPDH at 20 V for 7 min. All the membranes were blocked in TBST bufferwith 5% nonfat dry milk in at RT for 1 h and then incubated with primaryantibody anti-COL1A1 and anti-α-SMA in TBST buffer containing 5% BSA at4° C. overnight. For GAPDH detection, the membrane with α-SMAimmunoblots were stripped with Restore™ Western Blot Stripping Bufferafter detection. And the membranes were re-blocked and then re-probedwith primary antibody anti-GAPDH antibody at room temperature (RT) for 2h. After incubation with primary antibodies, membranes were washed withTBST, then incubated with the secondary antibody at RT for 1 h. Blotswere visualized using the instrument Image Quant LAS-4000. Thechemiluminescent signals derived from ECL Western blotting reagents werecaptured. The bands integrated intensity from 16-bit blot images wasused for quantitation with the software (1D component of ImageQuant TL).The quantification raw data of the two duplicated gels was obtained fromImageQuant TL. Collagen I and α-SMA proteins expression level wasnormalized to GAPDH for each gel. The average normalization data of thetwo duplicated gels was calculated and applied to calculate IC₅₀ usingan equation for a sigmoidal dose response (variable slope) of GraphPad™Prism software. The equation is Y=Bottom+(Top−Bottom)/(1+10{circumflexover ( )}((Log IC50−X)*Hillslope). Note: X is the logarithm of compoundconcentration, Y is the average normalization data

Table 4 include IC₅₀ values for collagen of selected compounds;compounds having an IC₅₀ value of <0.1 nM as +++, 0.1-1.0 nM as ++,and >1.0 nM as +.

TABLE 4 IC₅₀ data for collagen in LX-2 cells Collagen in LX-2 Compound #(IC₅₀, nM) 172 +++ 128 ++ 131 ++ 127 ++ 125 ++ 188 ++ 159 ++ 121 .+++196 +++ 193 +++ 112 +++ 126 ++ 117 ++ 189 ++ 116 ++ 153 .++ 190 +++ 185++ 191 ++ 167 +++ 111 ++ 156 +++ 194 ++ 146 ++ 150 ++ 139 ++ 120 +++ 192+++ 130 ++  1

+  4

+  39

+

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1-29. (canceled)
 30. A compound represented by Formula (IIA),

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom substituted C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is substitutedwith one or more substituents selected from halogen, —OH, —CN, —NO₂,—NH₂, oxo, ═S, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl,—O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle; and optionallysubstituted 3 to 8-membered heterocycle, wherein the 3 to 8-memberedheterocycle is optionally substituted with one or more substituentsselected from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, —S(O₂)NH₂, —C₁₋₁₀haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂carbocycle, 3- to 12-membered heterocycle, and optionally substitutedC₁₋₁₀ alkyl, wherein the C₁₋₁₀ alkyl is optionally substituted with oneor more substituents selected from hydroxy, halogen, oxo, —C₁₋₁₀haloalkyl, —NH₂, —CN, and —NO₂; R³ is optionally substituted C₃₋₁₀carbocycle, which is optionally substituted with one or moresubstituents selected from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S, C₁₋₆alkyl, —C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; and R⁴ issubstituted C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is substituted with oneor more halogen.
 31. The compound of claim 30, wherein R⁴ is substitutedwith two fluorine.
 32. The compound of claim 30, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is selected from


33. The compound of claim 30, or a pharmaceutically acceptable saltthereof, wherein R³ is substituted C₆ carbocycle, and wherein the C₆carbocycle is substituted with one or more substituents selected fromhalogen and —C₁₋₁₀ haloalkyl.
 34. The compound of claim 30, or apharmaceutically acceptable salt thereof, wherein R¹ is substitutedC₁-C₆ alkyl, wherein the C₁-C₆ alkyl is substituted with one or moresubstituents selected from halogen, —OH, —CN, —NO₂, —NH₂, oxo, ═S,—C₁₋₁₀ haloalkyl, —O—C₁₋₁₀ alkyl, —O—C₁₋₆alkyl-O—C(O)(O—C₁₋₁₀ alkyl),C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle.
 35. The compound of claim 34, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is optionally substituted with oneor more substituents selected from oxo, halogen, —O—C₁₋₁₀ alkyl, —C₁₋₁₀haloalkyl, and —OH.
 36. The compound of claim 34, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is optionally substituted with oneor more substituents selected from —OH, oxo, and —O—C₁₋₁₀ alkyl.
 37. Thecompound of claim 34, or a pharmaceutically acceptable salt thereof,wherein R¹ is


38. The compound of claim 34, or a pharmaceutically acceptable saltthereof, wherein R¹ is


39. The compound of claim 31, or a pharmaceutically acceptable saltthereof, wherein R¹ is an optionally substituted bicyclic heterocycle.40. The compound of claim 39, or a pharmaceutically acceptable saltthereof, wherein R¹ is an optionally substituted bridged bicyclicheterocycle.
 41. The compound of claim 39, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is


42. A method of treating a fibrotic disease or condition, comprisingadministering a compound of claim 30 or a pharmaceutically acceptablesalt thereof, to a subject in need thereof.
 43. The method of claim 42,wherein the fibrotic disease or condition is kidney fibrosis.
 44. Themethod of claim 42, wherein the fibrotic disease or condition isassociated with TNIK kinase.
 45. A pharmaceutical composition comprising(i) a compound of claim 30 or a pharmaceutically acceptable saltthereof; and (ii) a pharmaceutically acceptable excipient.